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Michael Barry Kastan

William and Jane Shingleton Distinguished Professor of Pharmacology and Cancer Biology
Pharmacology & Cancer Biology
DUMC Box 3917, 10 Bryan Searle Drive, Rm 422, Durham, NC 27710
DUMC Box 3917, 10 Bryan Searle Drive, Rm 422, Durham, NC 27710

Selected Publications


A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors.

Journal Article Mol Cancer Ther · June 4, 2024 A majority of patients with cancer receive radiotherapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiothera ... Full text Link to item Cite

Participation of ATM, SMG1, and DDX5 in a DNA Damage-Induced Alternative Splicing Pathway.

Journal Article Radiat Res · April 1, 2023 Altered cellular responses to DNA damage can contribute to cancer development, progression, and therapeutic resistance. Mutations in key DNA damage response factors occur across many cancer types, and the DNA damage-responsive gene, TP53, is frequently mut ... Full text Link to item Cite

ATM Regulation of the Cohesin Complex Is Required for Repression of DNA Replication and Transcription in the Vicinity of DNA Double-Strand Breaks.

Journal Article Mol Cancer Res · March 1, 2023 Multiple members of the cohesin complex are involved in the regulation of DNA replication and transcription in the vicinity of DNA double-strand breaks and their role(s) are regulated by the ATM kinase. ... Full text Link to item Cite

Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia.

Journal Article iScience · January 22, 2021 There is evidence that ATM mutated in ataxia-telangiectasia (A-T) plays a key role in protecting against mitochondrial dysfunction, the mechanism for which remains unresolved. We demonstrate here that ATM-deficient cells are exquisitely sensitive to nutrie ... Full text Link to item Cite

DNA-Damage-Induced Alternative Splicing of p53.

Journal Article Cancers (Basel) · January 12, 2021 Cellular responses to DNA damage and other stresses are important determinants of mutagenesis and impact the development of a wide range of human diseases. TP53 is highly mutated in human cancers and plays an essential role in stress responses and cell fat ... Full text Link to item Cite

Retrospective Diagnosis of Ataxia-Telangiectasia in an Adolescent Patient With a Remote History of T-Cell Leukemia.

Journal Article J Pediatr Hematol Oncol · January 2021 Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar degeneration that is typically diagnosed in early childhood. A-T is associated with a predisposition to malignancies, particularly lymphoid tumors in ... Full text Link to item Cite

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.

Journal Article Diabetol Metab Syndr · 2019 BACKGROUND: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalaria ... Full text Link to item Cite

Abeloff’s Clinical Oncology

Book · January 1, 2019 Easily accessible and clinically focused, Abeloff’s Clinical Oncology, 6th Edition, covers recent advances in our understanding of the pathophysiology of cancer, cellular and molecular causes of cancer initiation and progression, new and emerging therapies ... Full text Cite

Preface

Book · January 1, 2019 Full text Cite

DNA Damage Response Pathways and Cancer

Chapter · January 1, 2019 DNA repair and the cellular response to DNA damage are critical for maintaining genomic stability. Defects in DNA repair or the response to DNA damage encountered from endogenous or external sources results in an increased rate of genetic mutations, often ... Full text Cite

Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers.

Journal Article Cancer Discov · July 2017 Cellular responses to DNA damage are critical determinants of cancer development and aging-associated pathogenesis. Here, we identify and characterize a DNA-damage response (DDR) pathway that regulates alternative splicing of numerous gene products, includ ... Full text Link to item Cite

Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells.

Journal Article Cell Res · June 2017 DNA double-strand breaks (DSBs) are traditionally associated with cancer through their abilities to cause chromosomal instabilities or gene mutations. Here we report a new class of self-inflicted DNA DSBs that can drive tumor growth irrespective of their e ... Full text Link to item Cite

Abstract IA17: Non-canonical aspects of ATM and p53 signaling pathways

Conference Molecular Cancer Research · April 1, 2017 AbstractThe ATM protein kinase and p53 protein are both central mediators of many aspects of DNA damage and cellular stress signaling. While there is a clear, direct relationship between ATM and p53, ATM has ... Full text Cite

Perspectives from man's best friend: National Academy of Medicine's Workshop on Comparative Oncology.

Journal Article Sci Transl Med · February 3, 2016 Scientists gather to survey comparative oncology research and pinpoint potential contributions to human therapeutics. ... Full text Link to item Cite

Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents.

Journal Article J Med Chem · January 28, 2016 We previously reported a novel inhibitor of the ataxia-telangiectasia mutated (ATM) kinase, which is a target for novel radiosensitizing drugs. While our initial lead, compound 4, was relatively potent and nontoxic, it exhibited poor stability to oxidative ... Full text Link to item Cite

Chromatin perturbations during the DNA damage response in higher eukaryotes.

Journal Article DNA Repair (Amst) · December 2015 The DNA damage response is a widely used term that encompasses all signaling initiated at DNA lesions and damaged replication forks as it extends to orchestrate DNA repair, cell cycle checkpoints, cell death and senescence. ATM, an apical DNA damage signal ... Full text Link to item Cite

ATM functions at the peroxisome to induce pexophagy in response to ROS.

Journal Article Nat Cell Biol · October 2015 Peroxisomes are highly metabolic, autonomously replicating organelles that generate reactive oxygen species (ROS) as a by-product of fatty acid β-oxidation. Consequently, cells must maintain peroxisome homeostasis, or risk pathologies associated with too f ... Full text Link to item Cite

Repair versus Checkpoint Functions of BRCA1 Are Differentially Regulated by Site of Chromatin Binding.

Journal Article Cancer Res · July 1, 2015 The product of the Brca1 tumor-suppressor gene is involved in multiple aspects of the cellular DNA damage response (DDR), including activation of cell-cycle arrests and DNA double-stranded break (DSB) repair by homologous recombination. Prior reports demon ... Full text Link to item Cite

A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors.

Journal Article Mol Cancer Ther · June 4, 2024 A majority of patients with cancer receive radiotherapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiothera ... Full text Link to item Cite

Participation of ATM, SMG1, and DDX5 in a DNA Damage-Induced Alternative Splicing Pathway.

Journal Article Radiat Res · April 1, 2023 Altered cellular responses to DNA damage can contribute to cancer development, progression, and therapeutic resistance. Mutations in key DNA damage response factors occur across many cancer types, and the DNA damage-responsive gene, TP53, is frequently mut ... Full text Link to item Cite

ATM Regulation of the Cohesin Complex Is Required for Repression of DNA Replication and Transcription in the Vicinity of DNA Double-Strand Breaks.

Journal Article Mol Cancer Res · March 1, 2023 Multiple members of the cohesin complex are involved in the regulation of DNA replication and transcription in the vicinity of DNA double-strand breaks and their role(s) are regulated by the ATM kinase. ... Full text Link to item Cite

Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia.

Journal Article iScience · January 22, 2021 There is evidence that ATM mutated in ataxia-telangiectasia (A-T) plays a key role in protecting against mitochondrial dysfunction, the mechanism for which remains unresolved. We demonstrate here that ATM-deficient cells are exquisitely sensitive to nutrie ... Full text Link to item Cite

DNA-Damage-Induced Alternative Splicing of p53.

Journal Article Cancers (Basel) · January 12, 2021 Cellular responses to DNA damage and other stresses are important determinants of mutagenesis and impact the development of a wide range of human diseases. TP53 is highly mutated in human cancers and plays an essential role in stress responses and cell fat ... Full text Link to item Cite

Retrospective Diagnosis of Ataxia-Telangiectasia in an Adolescent Patient With a Remote History of T-Cell Leukemia.

Journal Article J Pediatr Hematol Oncol · January 2021 Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar degeneration that is typically diagnosed in early childhood. A-T is associated with a predisposition to malignancies, particularly lymphoid tumors in ... Full text Link to item Cite

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.

Journal Article Diabetol Metab Syndr · 2019 BACKGROUND: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalaria ... Full text Link to item Cite

Abeloff’s Clinical Oncology

Book · January 1, 2019 Easily accessible and clinically focused, Abeloff’s Clinical Oncology, 6th Edition, covers recent advances in our understanding of the pathophysiology of cancer, cellular and molecular causes of cancer initiation and progression, new and emerging therapies ... Full text Cite

Preface

Book · January 1, 2019 Full text Cite

DNA Damage Response Pathways and Cancer

Chapter · January 1, 2019 DNA repair and the cellular response to DNA damage are critical for maintaining genomic stability. Defects in DNA repair or the response to DNA damage encountered from endogenous or external sources results in an increased rate of genetic mutations, often ... Full text Cite

Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers.

Journal Article Cancer Discov · July 2017 Cellular responses to DNA damage are critical determinants of cancer development and aging-associated pathogenesis. Here, we identify and characterize a DNA-damage response (DDR) pathway that regulates alternative splicing of numerous gene products, includ ... Full text Link to item Cite

Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells.

Journal Article Cell Res · June 2017 DNA double-strand breaks (DSBs) are traditionally associated with cancer through their abilities to cause chromosomal instabilities or gene mutations. Here we report a new class of self-inflicted DNA DSBs that can drive tumor growth irrespective of their e ... Full text Link to item Cite

Abstract IA17: Non-canonical aspects of ATM and p53 signaling pathways

Conference Molecular Cancer Research · April 1, 2017 AbstractThe ATM protein kinase and p53 protein are both central mediators of many aspects of DNA damage and cellular stress signaling. While there is a clear, direct relationship between ATM and p53, ATM has ... Full text Cite

Perspectives from man's best friend: National Academy of Medicine's Workshop on Comparative Oncology.

Journal Article Sci Transl Med · February 3, 2016 Scientists gather to survey comparative oncology research and pinpoint potential contributions to human therapeutics. ... Full text Link to item Cite

Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents.

Journal Article J Med Chem · January 28, 2016 We previously reported a novel inhibitor of the ataxia-telangiectasia mutated (ATM) kinase, which is a target for novel radiosensitizing drugs. While our initial lead, compound 4, was relatively potent and nontoxic, it exhibited poor stability to oxidative ... Full text Link to item Cite

Chromatin perturbations during the DNA damage response in higher eukaryotes.

Journal Article DNA Repair (Amst) · December 2015 The DNA damage response is a widely used term that encompasses all signaling initiated at DNA lesions and damaged replication forks as it extends to orchestrate DNA repair, cell cycle checkpoints, cell death and senescence. ATM, an apical DNA damage signal ... Full text Link to item Cite

ATM functions at the peroxisome to induce pexophagy in response to ROS.

Journal Article Nat Cell Biol · October 2015 Peroxisomes are highly metabolic, autonomously replicating organelles that generate reactive oxygen species (ROS) as a by-product of fatty acid β-oxidation. Consequently, cells must maintain peroxisome homeostasis, or risk pathologies associated with too f ... Full text Link to item Cite

Repair versus Checkpoint Functions of BRCA1 Are Differentially Regulated by Site of Chromatin Binding.

Journal Article Cancer Res · July 1, 2015 The product of the Brca1 tumor-suppressor gene is involved in multiple aspects of the cellular DNA damage response (DDR), including activation of cell-cycle arrests and DNA double-stranded break (DSB) repair by homologous recombination. Prior reports demon ... Full text Link to item Cite

HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism.

Journal Article Radiat Res · June 2015 Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy. While hypoxia increases tumor cell survival after radiation exposure because there is less oxygen to oxidize damaged DNA, it remains unclear ... Full text Link to item Cite

The DNA damage response: implications for tumor responses to radiation and chemotherapy.

Journal Article Annu Rev Med · 2015 Cellular responses to DNA damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy. Identification of molecular pathways governing DNA damage signaling and DNA repair in response to differ ... Full text Link to item Cite

The scaffold protein WRAP53β orchestrates the ubiquitin response critical for DNA double-strand break repair.

Journal Article Genes Dev · December 15, 2014 The WD40 domain-containing protein WRAP53β (WD40 encoding RNA antisense to p53; also referred to as WDR79/TCAB1) controls trafficking of splicing factors and the telomerase enzyme to Cajal bodies, and its functional loss has been linked to carcinogenesis, ... Full text Link to item Cite

Abstract IA11: New insights into DNA double-strand break responses

Conference Cancer Research · December 1, 2014 AbstractRepair of damaged DNA in cells is complicated by the necessity to repair the damage in the context of complex chromatin structures. Elucidation of molecular mechanisms of DNA repair in intact cells h ... Full text Cite

Abstract IA08: Ataxia-telangiectasia: Broad implications from the study of a rare disease

Journal Article Cancer Research · October 15, 2014 AbstractDNA damage signaling pathways are critical mediators of both tumor development and tumor responses to chemotherapy and radiation therapy. Significant progress has been made in recent years in elucida ... Full text Cite

Inactivation of the human papillomavirus E6 or E7 gene in cervical carcinoma cells by using a bacterial CRISPR/Cas RNA-guided endonuclease.

Journal Article J Virol · October 2014 High-risk human papillomaviruses (HPVs), including HPV-16 and HPV-18, are the causative agents of cervical carcinomas and are linked to several other tumors of the anogenital and oropharyngeal regions. The majority of HPV-induced tumors contain integrated ... Full text Link to item Cite

Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks.

Journal Article EMBO J · April 16, 2014 The MRE11-RAD50-NBS1 (MRN) complex is essential for the detection of DNA double-strand breaks (DSBs) and initiation of DNA damage signaling. Here, we show that Rad17, a replication checkpoint protein, is required for the early recruitment of the MRN comple ... Full text Link to item Cite

Development of a cell-based, high-throughput screening assay for ATM kinase inhibitors.

Journal Article J Biomol Screen · April 2014 The ATM (ataxia-telangiectasia, mutated) protein kinase is a major regulator of cellular responses to DNA double-strand breaks (DSBs), DNA lesions that can be caused by ionizing irradiation (IR), oxidative damage, or exposure to certain chemical agents. In ... Full text Link to item Cite

Pilot study of modified LMB-based therapy for children with ataxia-telangiectasia and advanced stage high grade mature B-cell malignancies.

Journal Article Pediatr Blood Cancer · February 2014 Children with ataxia-telangiectasia (A-T) and cancer have a poorer prognosis due in part to increased treatment-related toxicity. We piloted a curative intent approach in five children with A-T who presented with advanced stage (III, n = 2; IV, n = 3) B-NH ... Full text Link to item Cite

Preface

Book · January 1, 2014 Full text Cite

Abeloff's Clinical Oncology: Fifth Edition

Book · October 22, 2013 Practical and clinically focused, Abeloff's Clinical Oncology is a trusted medical reference book designed to capture the latest scientific discoveries and their implications for cancer diagnosis and management of cancer in the most accessible manner possi ... Cite

Nucleolin mediates nucleosome disruption critical for DNA double-strand break repair.

Journal Article Proc Natl Acad Sci U S A · October 15, 2013 Recruitment of DNA repair factors and modulation of chromatin structure at sites of DNA double-strand breaks (DSBs) is a complex and highly orchestrated process. We developed a system that can induce DSBs rapidly at defined endogenous sites in mammalian ge ... Full text Link to item Cite

A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS.

Journal Article Nat Cell Biol · October 2013 Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signalling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxyg ... Full text Link to item Cite

Strategies for optimizing the response of cancer and normal tissues to radiation.

Journal Article Nat Rev Drug Discov · July 2013 Approximately 50% of all patients with cancer receive radiation therapy at some point during the course of their treatment, and the majority of these patients are treated with curative intent. Despite recent advances in the planning of radiation treatment ... Full text Link to item Cite

A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS

Journal Article Nature Cell Biology · 2013 Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signalling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxyg ... Full text Cite

A message from the Editor-in-Chief.

Journal Article Mol Cancer Res · December 2012 Full text Link to item Cite

Chloroquine improves survival and hematopoietic recovery after lethal low-dose-rate radiation.

Journal Article Int J Radiat Oncol Biol Phys · November 1, 2012 PURPOSE: We have previously shown that the antimalarial agent chloroquine can abrogate the lethal cellular effects of low-dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate th ... Full text Link to item Cite

Interactions of nucleolin and ribosomal protein L26 (RPL26) in translational control of human p53 mRNA.

Journal Article J Biol Chem · May 11, 2012 Ribosomal protein RPL26 enhances p53 translation after DNA damage, and this regulation depends upon interactions between the 5'- and 3'-UTRs of human p53 mRNA (Takagi, M., Absalon, M. J., McLure, K. G., and Kastan, M. B. (2005) Cell 123, 49-63; Chen, J., a ... Full text Link to item Cite

A new role for ATM: regulating mitochondrial function and mitophagy.

Journal Article Autophagy · May 1, 2012 The various pathologies in ataxia telangiectasia (A-T) patients including T-cell lymphomagenesis have been attributed to defects in the DNA damage response pathway because ATM, the gene mutated in this disease, is a key mediator of this process. Analysis o ... Full text Link to item Cite

Autophagy links inflammasomes to atherosclerotic progression.

Journal Article Cell Metab · April 4, 2012 We investigated the role of autophagy in atherosclerosis. During plaque formation in mice, autophagic markers colocalized predominantly with macrophages (mφ). Atherosclerotic aortas had elevated levels of p62, suggesting that dysfunctional autophagy is cha ... Full text Link to item Cite

Optimizing ATM inhibitor activity and specificity using pharmacophore-based docking

Conference ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY · March 25, 2012 Link to item Cite

Mitochondrial dysfunction in ataxia-telangiectasia.

Journal Article Blood · February 9, 2012 Ataxia-telangiectasia mutated (ATM) plays a central role in DNA damage responses, and its loss leads to development of T-cell malignancies. Here, we show that ATM loss also leads to intrinsic mitochondrial abnormalities in thymocytes, including elevated re ... Full text Link to item Cite

Chloroquine Activates ATM and Improves Hematopoietic Recovery and Survival of Mice following Low Dose-rate Radiation

Journal Article International Journal of Radiation Oncology*Biology*Physics · October 2011 Full text Cite

Abstract 3086: Interactions of nucleolin and ribosomal protein RPL26 in the translational control of human p53 mRNA

Journal Article Cancer Research · April 15, 2011 AbstractOur lab has previously shown that the ribosomal protein RPL26 enhances p53 translation and induction after DNA damage and that this regulation depends upon interactions between the 5′ and 3′ untransl ... Full text Cite

5'-3'-UTR interactions regulate p53 mRNA translation and provide a target for modulating p53 induction after DNA damage.

Journal Article Genes Dev · October 1, 2010 Optimal induction of p53 protein after DNA damage requires RPL26-mediated increases in p53 mRNA translation. We report here the existence of a dsRNA region containing complementary sequences of the 5'- and 3'-untranslated regions (UTRs) of human p53 mRNA t ... Full text Link to item Cite

Multiple roles of ATM in monitoring and maintaining DNA integrity.

Journal Article FEBS Lett · September 10, 2010 The ability of our cells to maintain genomic integrity is fundamental for protection from cancer development. Central to this process is the ability of cells to recognize and repair DNA damage and progress through the cell cycle in a regulated and orderly ... Full text Link to item Cite

Deficient innate immunity, thymopoiesis, and gene expression response to radiation in survivors of childhood acute lymphoblastic leukemia.

Journal Article Cancer Epidemiol · June 2010 BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) are at an increased risk of developing secondary malignant neoplasms. Radiation and chemotherapy can cause mutations and cytogenetic abnormalities and induce genomic instability. Host im ... Full text Link to item Cite

Abstract 4831: ATM signals to TSC2 in the cytoplasm to regulate mTORC1 and autophagy in response to ROS

Journal Article Cancer Research · April 15, 2010 AbstractATM is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. ATM deficiency is also associated with increased oxidati ... Full text Cite

The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis.

Journal Article Immunity · March 26, 2010 Decreased expression of the Nlrp3 protein is associated with susceptibility to Crohn's disease. However, the role of Nlrp3 in colitis has not been characterized. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, which are ... Full text Link to item Cite

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS.

Journal Article Proc Natl Acad Sci U S A · March 2, 2010 Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency ... Full text Link to item Cite

Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26.

Journal Article Mol Cell · October 24, 2008 Mdm2 regulates the p53 tumor suppressor by promoting its proteasome-mediated degradation. Mdm2 and p53 engage in an autoregulatory feedback loop that maintains low p53 activity in nonstressed cells. We now report that Mdm2 regulates p53 levels also by targ ... Full text Link to item Cite

Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation.

Journal Article Cancer Res · September 15, 2008 In response to DNA damage, the ATM protein kinase activates signal transduction pathways essential for coordinating cell cycle progression with DNA repair. In the human disease ataxia-telangiectasia, mutation of the ATM gene results in multiple cellular de ... Full text Link to item Cite

Human T-cell leukemia virus type 1 tax attenuates the ATM-mediated cellular DNA damage response.

Journal Article J Virol · July 2008 Genomic instability, a hallmark of leukemic cells, is associated with malfunctioning cellular responses to DNA damage caused by defective cell cycle checkpoints and/or DNA repair. Adult T-cell leukemia, which can result from infection with human T-cell leu ... Full text Link to item Cite

A novel ATM-dependent pathway regulates protein phosphatase 1 in response to DNA damage.

Journal Article Mol Cell Biol · April 2008 Protein phosphatase 1 (PP1), a major protein phosphatase important for a variety of cellular responses, is activated in response to ionizing irradiation (IR)-induced DNA damage. Here, we report that IR induces the rapid dissociation of PP1 from its regulat ... Full text Link to item Cite

DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture.

Journal Article Mol Cancer Res · April 2008 Significant progress has been made in recent years in elucidating the molecular controls of cellular responses to DNA damage in mammalian cells. Much of our understanding of the mechanisms involved in cellular DNA damage response pathways has come from stu ... Full text Link to item Cite

Assessment of protein dynamics and DNA repair following generation of DNA double-strand breaks at defined genomic sites.

Journal Article Nat Protoc · 2008 The formation of protein aggregates (foci) at sites of DNA double-strand breaks (DSBs) is mainly studied by immunostaining and is hence limited by the low resolution of light microscopy and the availability of appropriate and selective antibodies. Here, we ... Full text Link to item Cite

Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis.

Journal Article J Clin Invest · January 2008 Despite great interest in cancer chemoprevention, effective agents are few. Here we show that chloroquine, a drug that activates the stress-responsive Atm-p53 tumor-suppressor pathway, preferentially enhances the death of Myc oncogene-overexpressing primar ... Full text Link to item Cite

Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis.

Journal Article Cancer Res · December 15, 2007 The use of agents to prevent the onset of and/or the progression to breast cancer has the potential to lower breast cancer risk. We have previously shown that the tumor-suppressor gene p53 is a potential mediator of hormone (estrogen/progesterone)-induced ... Full text Link to item Cite

A message from the editor

Journal Article Molecular Cancer Research · November 1, 2007 Cite

Atm deficiency affects both apoptosis and proliferation to augment Myc-induced lymphomagenesis.

Journal Article Mol Cancer Res · July 2007 Myc oncoproteins are commonly activated in malignancies and are sufficient to provoke many types of cancer. However, the critical mechanisms by which Myc contributes to malignant transformation are not clear. DNA damage seems to be an important initiating ... Full text Link to item Cite

Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair.

Journal Article Nat Cell Biol · June 2007 We developed a novel system to create DNA double-strand breaks (DSBs) at defined endogenous sites in the human genome, and used this system to detect protein recruitment and loss at and around these breaks by chromatin immunoprecipitation (ChIP). The detec ... Full text Link to item Cite

p53: a two-faced cancer gene.

Journal Article Nat Cell Biol · May 2007 Full text Link to item Cite

Wild-type p53: tumors can't stand it.

Journal Article Cell · March 9, 2007 Most malignant tumors disrupt the p53 signaling pathway in order to grow and survive. Although many genes in addition to p53 are mutated in tumors, recent studies by Ventura et al. (2007) and Xue et al. (2007) suggest that restoring p53 function alone is s ... Full text Link to item Cite

Our cells get stressed too! Implications for human disease.

Journal Article Blood Cells Mol Dis · 2007 Significant progress has been made in recent years elucidating the molecular controls of cellular responses to DNA damage in mammalian cells. Many of the insights that we have gained into the mechanisms involved in cellular DNA damage response pathways hav ... Full text Link to item Cite

Editor's note

Journal Article Molecular Cancer Research · January 1, 2007 Cite

ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome.

Journal Article Cell Metab · November 2006 Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, inc ... Full text Link to item Cite

A subtle t(3;8) results in plausible juxtaposition of MYC and BCL6 in a child with Burkitt lymphoma/leukemia and ataxia-telangiectasia.

Journal Article Cancer Genet Cytogenet · July 1, 2006 Translocations involving 3q27 that affect the BCL6 gene are common and specific chromosomal abnormalities in B-cell precursor non-Hodgkin lymphoma (mainly diffuse large-cell and follicular lymphoma), but they have not been reported in Burkitt lymphoma. Her ... Full text Link to item Cite

Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks.

Journal Article J Cell Biol · April 24, 2006 We show that DNA double-strand breaks (DSBs) induce complex subcompartmentalization of genome surveillance regulators. Chromatin marked by gamma-H2AX is occupied by ataxia telangiectasia-mutated (ATM) kinase, Mdc1, and 53BP1. In contrast, repair factors (R ... Full text Link to item Cite

The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor.

Journal Article Genes Dev · December 15, 2005 Genetic and cytologic data from Saccharomyces cerevisiae and mammals implicate the Mre11 complex, consisting of Mre11, Rad50, and Nbs1, as a sensor of DNA damage, and indicate that the complex influences the activity of ataxia-telangiectasia mutated (ATM) ... Full text Link to item Cite

Cell biology: A BID for the pathway.

Journal Article Nature · October 20, 2005 Full text Link to item Cite

DNA damage responses: Cancer and beyond

Journal Article Scientist · October 10, 2005 Cite

Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin.

Journal Article Cell · October 7, 2005 Increases in p53 protein levels after DNA damage have largely been attributed to an increase in the half-life of p53 protein. Here we demonstrate that increased translation of p53 mRNA is also a critical step in the induction of p53 protein in irradiated c ... Full text Link to item Cite

ATM activation in normal human tissues and testicular cancer.

Journal Article Cell Cycle · June 2005 The ATM kinase is a tumor suppressor and key regulator of biological responses to DNA damage. Cultured cells respond to genotoxic insults that induce DNA double-strand breaks by prompt activation of ATM through its autophosphorylation on serine 1981. Howev ... Full text Link to item Cite

20 years of DNA damage signaling to p53

Chapter · January 1, 2005 The short history of p53 contains an overwhelming number of facts and hypotheses, presenting the challenge of integrating diverse and sometimes mutually exclusive ideas into a coherent picture. It is important to make a distinction between p53 tumor suppre ... Full text Cite

The ATM-dependent DNA damage signaling pathway.

Journal Article Cold Spring Harb Symp Quant Biol · 2005 Many of the insights that we have gained into the mechanisms involved in cellular DNA damage response pathways have come from studies of human cancer susceptibility syndromes that are altered in DNA damage responses. ATM, the gene mutated in the disorder, ... Full text Link to item Cite

Cell-cycle checkpoints and cancer.

Journal Article Nature · November 18, 2004 All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation. Highly conserved DNA-repair and cell-cycle checkpoint pathways allow cells to deal with both endogenous and exogenous sources of DNA damage. How much an ... Full text Link to item Cite

NAD+ modulates p53 DNA binding specificity and function.

Journal Article Mol Cell Biol · November 2004 DNA damage induces p53 DNA binding activity, which affects tumorigenesis, tumor responses to therapies, and the toxicities of cancer therapies (B. Vogelstein, D. Lane, and A. J. Levine, Nature 408:307-310, 2000; K. H. Vousden and X. Lu, Nat. Rev. Cancer 2: ... Full text Link to item Cite

BRCA1 is required for common-fragile-site stability via its G2/M checkpoint function.

Journal Article Mol Cell Biol · August 2004 Common fragile sites are loci that form chromosome gaps or breaks when DNA synthesis is partially inhibited. Fragile sites are prone to deletions, translocations, and other rearrangements that can cause the inactivation of associated tumor suppressor genes ... Full text Link to item Cite

The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response.

Journal Article PLoS Biol · August 2004 The telomeric protein TRF2 is required to prevent mammalian telomeres from activating DNA damage checkpoints. Here we show that overexpression of TRF2 affects the response of the ATM kinase to DNA damage. Overexpression of TRF2 abrogated the cell cycle arr ... Full text Link to item Cite

Initiating cellular stress responses.

Journal Article Cell · July 9, 2004 The phosphoinositide 3-kinase related kinases (PIKKs) mediate responses to diverse stresses, including DNA double-strand breaks (DSBs), abnormal replication fork progression, the recognition of premature termination codons in mRNAs, and inadequate nutrient ... Full text Link to item Cite

Phosphatases join kinases in DNA-damage response pathways.

Journal Article Trends Cell Biol · July 2004 An inappropriate imbalance of kinase and phosphatase activities could be deleterious to cellular processes such as proliferation. Cellular responses to DNA damage use signal-transduction pathways involving phosphorylation events, and such modifications mus ... Full text Link to item Cite

Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1 pathway.

Journal Article Genes Dev · June 15, 2004 The ATM protein kinase is activated by intermolecular autophosphorylation in response to DNA damage and initiates cellular signaling pathways that facilitate cell survival and reduce chromosomal breakage. Here, we show that NBS1 and BRCA1 are required for ... Full text Link to item Cite

Disappearance of the telomere dysfunction-induced stress response in fully senescent cells.

Journal Article Cancer Res · June 1, 2004 Replicative senescence is a natural barrier to cellular proliferation that is triggered by telomere erosion and dysfunction. Here, we demonstrate that ATM activation and H2AX-gamma nuclear focus formation are sensitive markers of telomere dysfunction in pr ... Full text Link to item Cite

Chromatin association of rad17 is required for an ataxia telangiectasia and rad-related kinase-mediated S-phase checkpoint in response to low-dose ultraviolet radiation.

Journal Article Mol Cancer Res · June 2004 Activation of the S-phase checkpoint results in an inhibition of DNA synthesis in response to DNA damage. This is an active cellular response that may enhance cell survival and limit heritable genetic abnormalities. While much attention has been paid to el ... Link to item Cite

Distinct functional domains of Nbs1 modulate the timing and magnitude of ATM activation after low doses of ionizing radiation.

Journal Article Oncogene · April 15, 2004 The ATM kinase is a tumour suppressor and a key activator of genome integrity checkpoints in mammalian cells exposed to ionizing radiation (IR) and other insults that elicit DNA double-strand breaks (DSBs). In response to IR, autophosphorylation on serine ... Full text Link to item Cite

Analyzing cell cycle checkpoints after ionizing radiation.

Journal Article Methods Mol Biol · 2004 Several methods to measure cell cycle perturbation after exposure to ionizing radiation are presented in this chapter. These methods include the G1 checkpoint assay by 5' bromode-oxyuridine (BrdUrd) labeling followed by flow cytometric analysis, the S-phas ... Full text Link to item Cite

ATM–the first step in helping cells deal with DNA damage

Journal Article Biomedicine & Pharmacotherapy · January 2004 Full text Cite

Molecular Cancer Research: A Note from the Editor

Journal Article Molecular Cancer Research · December 1, 2003 Cite

HSV-1 amplicon vector-mediated expression of ATM cDNA and correction of the ataxia-telangiectasia cellular phenotype.

Journal Article Gene Ther · August 2003 Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by neurodegeneration, immunodeficiency, cancer predisposition, genome instability, and radiation sensitivity. Previous research has shown that it is possible to correct the heredi ... Full text Link to item Cite

Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage.

Journal Article Mol Cancer Res · July 2003 Phosphorylation of NBS1, the product of the gene mutated in Nijmegen breakage syndrome (NBS), by ataxia telangiectasia mutated (ATM), the product of the gene mutated in ataxia telangiectasia, is required for activation of the S phase checkpoint in response ... Link to item Cite

DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.

Journal Article Nature · January 30, 2003 The ATM protein kinase, mutations of which are associated with the human disease ataxia-telangiectasia, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer or higher-order mul ... Full text Link to item Cite

Parc-ing p53 in the cytoplasm.

Journal Article Cell · January 10, 2003 Nikolaev et al. (this issue of Cell) report the identification of a parkin-like protein, Parc, and its role in anchoring the tumor suppressor protein p53 in the cytoplasm reveals yet another level of control of p53 function. Regulation of the subcellular l ... Full text Link to item Cite

Interaction of FANCD2 and NBS1 in the DNA damage response.

Journal Article Nat Cell Biol · December 2002 Fanconi anaemia (FA) and Nijmegen breakage syndrome (NBS) are autosomal recessive chromosome instability syndromes with distinct clinical phenotypes. Cells from individuals affected with FA are hypersensitive to mitomycin C (MMC), and cells from those with ... Full text Link to item Cite

Welcome to molecular cancer research

Journal Article Molecular Cancer Research · November 1, 2002 Cite

Phosphorylation of serine 1387 in Brca1 is specifically required for the Atm-mediated S-phase checkpoint after ionizing irradiation.

Journal Article Cancer Res · August 15, 2002 Although it is well established that inheritance of mutations in the Brca1 gene significantly increases the chances of developing breast or ovarian cancers, the mechanisms underlying this specific tumor susceptibility remain to be clarified. It is clear th ... Link to item Cite

Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways.

Journal Article Cell · May 17, 2002 Fanconi anemia (FA) and ataxia telangiectasia (AT) are clinically distinct autosomal recessive disorders characterized by spontaneous chromosome breakage and hematological cancers. FA cells are hypersensitive to mitomycin C (MMC), while AT cells are hypers ... Full text Link to item Cite

Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage.

Journal Article Genes Dev · March 1, 2002 Structural maintenance of chromosomes (SMC) proteins play important roles in sister chromatid cohesion, chromosome condensation, sex-chromosome dosage compensation, and DNA recombination and repair. Protein complexes containing heterodimers of the Smc1 and ... Full text Link to item Cite

Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation.

Journal Article Mol Cell Biol · February 2002 Cell cycle checkpoints are among the multiple mechanisms that eukaryotic cells possess to maintain genomic integrity and minimize tumorigenesis. Ionizing irradiation (IR) induces measurable arrests in the G(1), S, and G(2) phases of the mammalian cell cycl ... Full text Link to item Cite

Glioblastoma-related gene mutations and over-expression of functional epidermal growth factor receptors in SKMG-3 glioma cells.

Journal Article Acta Neuropathol · June 2001 Amplification of the epidermal growth factor receptor (EGFR) gene is found in about 40% of glioblastomas (GBMs) but is rarely detected in GBM cell lines. We confirmed that the exceptional SKMG-3 GBM cell line retained amplified EGFR genes in vitro, and fou ... Full text Link to item Cite

ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage.

Journal Article Genes Dev · May 1, 2001 The p53 tumor suppressor protein, a key regulator of cellular responses to genotoxic stress, is stabilized and activated after DNA damage. The rapid activation of p53 by ionizing radiation and radiomimetic agents is largely dependent on the ATM kinase. p53 ... Full text Link to item Cite

Involvement of Brca1 in S-phase and G(2)-phase checkpoints after ionizing irradiation.

Journal Article Mol Cell Biol · May 2001 Cell cycle arrests in the G(1), S, and G(2) phases occur in mammalian cells after ionizing irradiation and appear to protect cells from permanent genetic damage and transformation. Though Brca1 clearly participates in cellular responses to ionizing radiati ... Full text Link to item Cite

Cell cycle. Checking two steps.

Journal Article Nature · April 12, 2001 Full text Link to item Cite

Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation.

Journal Article Mol Cell Biol · February 2001 Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially reg ... Full text Link to item Cite

ATM--a key determinant of multiple cellular responses to irradiation.

Journal Article Acta Oncol · 2001 Ataxia-telangiectasia is a rare clinical disorder manifesting a variety of different abnormalities, including progressive neurodegeneration, increased cancer incidence, immune deficiency, sterility, and extreme radiosensitivity. Recent studies have demonst ... Full text Link to item Cite

ATM: genome stability, neuronal development, and cancer cross paths.

Journal Article Adv Cancer Res · 2001 One of the cornerstones of the web of signaling pathways governing cellular life and differentiation is the DNA damage response. It spans a complex network of pathways, ranging from DNA repair to modulation of numerous processes in the cell. DNA double-str ... Full text Link to item Cite

The many substrates and functions of ATM.

Journal Article Nat Rev Mol Cell Biol · December 2000 As its name suggests, the ATM--'ataxia-telangiectasia, mutated'--gene is responsible for the rare disorder ataxia-telangiectasia. Patients show various abnormalities, mainly in their responses to DNA damage, but also in other cellular processes. Although i ... Full text Link to item Cite

Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1.

Journal Article Nat Cell Biol · December 2000 One of the critical responses to insulin treatment is the stimulation of protein synthesis through induced phosphorylation of the eIF-4E-binding protein 1 (4E-BP1), and the subsequent release of the translation initiation factor, eIF-4E. Here we report tha ... Full text Link to item Cite

Cancer. A radical approach to treatment.

Journal Article Nature · September 21, 2000 Full text Link to item Cite

ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway.

Journal Article Nature · April 6, 2000 The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene, share a variety of phenotypic abnormalities such as chromosomal instability, radiation sensitivity ... Full text Link to item Cite

Ionizing radiation activates the ATM kinase throughout the cell cycle.

Journal Article Oncogene · March 9, 2000 The ATM protein kinase is a critical intermediate in a number of cellular responses to ionizing irradiation (IR) and possibly other stresses. ATM dysfunction results in abnormal checkpoint responses in multiple phases of the cell cycle, including G1, S and ... Full text Link to item Cite

Multiple signaling pathways involving ATM.

Journal Article Cold Spring Harb Symp Quant Biol · 2000 Full text Link to item Cite

Expression and assay of recombinant ATM.

Journal Article Methods Mol Biol · 2000 Full text Link to item Cite

Roles of TP53 and ATM in radiation responses

Conference RADIATION RESEARCH, VOL 2, CONGRESS PROCEEDINGS · January 1, 2000 Link to item Cite

Substrate specificities and identification of putative substrates of ATM kinase family members.

Journal Article J Biol Chem · December 31, 1999 Ataxia telangiectasia mutated (ATM) phosphorylates p53 protein in response to ionizing radiation, but the complex phenotype of AT cells suggests that it must have other cellular substrates as well. To identify substrates for ATM and the related kinases ATR ... Full text Link to item Cite

Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis.

Journal Article Leukemia · August 1999 The aromatic fatty acid phenylbutyrate (PB) induces cytostasis, differentiation, and apoptosis in primary myeloid leukemic cells at clinically achievable concentrations. In the present study, we have investigated the structural and cellular basis for PB-in ... Full text Link to item Cite

Molecular determinants of sensitivity to antitumor agents.

Journal Article Biochim Biophys Acta · July 29, 1999 Full text Link to item Cite

Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c.

Journal Article J Biol Chem · July 23, 1999 Caspases are cysteine proteases that mediate apoptosis by proteolysis of specific substrates. Although many caspase substrates have been identified, for most substrates the physiologic caspase(s) required for cleavage is unknown. The Bcl-2 protein, which i ... Full text Link to item Cite

Cytoprotective effects of hematopoietic growth factors on primary human acute myeloid leukemias are not mediated through changes in BCL-2, bax, or p21WAF1/CIP1.

Journal Article In Vivo · 1999 BACKGROUND: Hematopoietic growth factors (HGF) can suppress chemotherapy-induced programmed cell death (apoptosis) in hematopoietic cells. Although HGF can modulate the expression of apoptosis-regulatory genes, including bcl-2, bax, and p21WAF1/CIP1 in cel ... Link to item Cite

Loss of atm radiosensitizes multiple p53 null tissues.

Journal Article Cancer Res · December 15, 1998 An unusual clinical finding in ataxia-telangiectasia, a human disorder caused by mutations in atm, is exquisite sensitivity to gamma irradiation. By contrast, homozygous deletion of p53 is marked by radiation resistance in certain tissue compartments. Prev ... Link to item Cite

Defective potassium currents in ataxia telangiectasia fibroblasts.

Journal Article Genes Dev · December 1, 1998 Similarities exist between the progressive cerebellar ataxia in ataxia telangiectasia (AT) patients and a number of neurodegenerative diseases in both mouse and man involving specific mutations in ion channels and/or ion channel activity. These relationshi ... Full text Link to item Cite

Frequent detection of tumor cells in hematopoietic grafts in neuroblastoma and Ewing's sarcoma.

Journal Article Bone Marrow Transplant · November 1998 Many poor-risk neuroblastomas and tumours of the Ewing's sarcoma family (ET) recur despite autologous transplants. Recurrence may be due to tumor cells contained in the BM harvests or PBSC harvests. The objectives of this prospective study were to: (1) det ... Full text Link to item Cite

Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.

Journal Article Science · September 11, 1998 The p53 tumor suppressor protein is activated and phosphorylated on serine-15 in response to various DNA damaging agents. The gene product mutated in ataxia telangiectasia, ATM, acts upstream of p53 in a signal transduction pathway initiated by ionizing ra ... Full text Link to item Cite

Tumor-suppressor p53: implications for tumor development and prognosis.

Journal Article J Clin Oncol · September 1998 The p53 protein plays a central role in modulating cellular responses to cytotoxic stresses by contributing to both cell-cycle arrest and programmed cell death. Loss of p53 function during tumorigenesis can lead to inappropriate cell growth, increased cell ... Full text Link to item Cite

ATM binds to beta-adaptin in cytoplasmic vesicles.

Journal Article Proc Natl Acad Sci U S A · August 18, 1998 Inherited mutations in the ATM gene lead to a complex clinical phenotype characterized by neuronal degeneration, oculocutaneous telangiectasias, immune dysfunction, and cancer predisposition. Using the yeast two-hybrid system, we demonstrate that ataxia te ... Full text Link to item Cite

Human smooth muscle alpha-actin gene is a transcriptional target of the p53 tumor suppressor protein.

Journal Article Oncogene · March 12, 1998 Smooth muscle (sm) alpha-actin is expressed in vascular smooth muscle cells and fibroblast cells. Its expression is regulated by cell proliferation and repressed during oncogenic transformation. In this study, we demonstrate that p53 activation is associat ... Full text Link to item Cite

Small contribution of G1 checkpoint control manipulation to modulation of p53-mediated apoptosis.

Journal Article Oncogene · February 26, 1998 Deregulation of the S-phase promoting E2F-1 transcription factor has been shown to cooperate with p53 to induce apoptosis. BaF3 cells undergo rapid, p53-dependent apoptosis when irradiated in the absence of IL-3. Rapid apoptosis induced by ionizing radiati ... Full text Link to item Cite

Modulation of cell death by Bcl-XL through caspase interaction.

Journal Article Proc Natl Acad Sci U S A · January 20, 1998 The caspases are cysteine proteases that have been implicated in the execution of programmed cell death in organisms ranging from nematodes to humans. Many members of the Bcl-2 family, including Bcl-XL, are potent inhibitors of programmed cell death and in ... Full text Link to item Cite

Cellular survival pathways and resistance to cancer therapy.

Journal Article Drug Resist Updat · 1998 Chemotherapy and irradiation induce programmed cell death (apoptosis) in their target cells. Dysregulated apoptosis is a feature that is selected for during tumor formation and contributes to therapeutic resistance. Cell survival in the face of cytotoxic t ... Full text Link to item Cite

DNA damage induces phosphorylation of the amino terminus of p53.

Journal Article Genes Dev · December 15, 1997 Data are presented demonstrating that DNA damage leads to specific post-translational modifications of p53 protein. Using two-dimensional peptide mapping of in vivo radiolabeled p53 tryptic phosphopeptides, recombinant truncated p53 protein, and synthetic ... Full text Link to item Cite

Conversion of Bcl-2 to a Bax-like death effector by caspases.

Journal Article Science · December 12, 1997 Caspases are a family of cysteine proteases implicated in the biochemical and morphological changes that occur during apoptosis (programmed cell death). The loop domain of Bcl-2 is cleaved at Asp34 by caspase-3 (CPP32) in vitro, in cells overexpressing cas ... Full text Link to item Cite

Cell cycle and cell death after DNA damaye

Journal Article FASEB Journal · December 1, 1997 A variety of cellular responses to DNA damage influence cellular fate, such as whether heritable genetic alterations are passed on to daughter cells and whether the cell survives the damaging insult. The p53 and ATM gene products play critical roles in mod ... Cite

Influence of ATM function on telomere metabolism.

Journal Article Oncogene · November 27, 1997 The ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia, has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination and cell cycle control. The ATM gene has homology with the TEL ... Full text Link to item Cite

To oxidize or not to oxidize?

Journal Article Nat Med · November 1997 Full text Link to item Cite

p53 does not repress hypoxia-induced transcription of the vascular endothelial growth factor gene.

Journal Article Cancer Res · October 15, 1997 Hypoxia-induced neovascularization mediated by vascular endothelial growth factor (VEGF) contributes to tumor progression. Based on its effects when overexpressed in transient transfection assays, p53 has been proposed to repress VEGF transcription. To inv ... Link to item Cite

Rapamycin and p53 act on different pathways to induce G1 arrest in mammalian cells.

Journal Article Oncogene · October 2, 1997 Certain growth regulatory kinases contain a common domain related to the phospho-inositol 3 (PI-3) kinase catalytic site. These include the ATM gene product, DNA-PKcs, and the target of rapamycin (TOR in yeast; and FRAP in mammalian cells). Rapamycin inhib ... Full text Link to item Cite

On the TRAIL from p53 to apoptosis?

Journal Article Nat Genet · October 1997 Full text Link to item Cite

Untitled

Journal Article CLINICAL CANCER RESEARCH · September 1, 1997 Link to item Cite

Dissociation of radiation-induced phosphorylation of replication protein A from the S-phase checkpoint.

Journal Article Cancer Res · August 15, 1997 Replication protein A (RPA) is a trimeric single-stranded DNA-binding protein complex involved in DNA replication, repair, and recombination. DNA damage induces phosphorylation of the RPA p34 subunit, and it has been speculated that this phosphorylation co ... Link to item Cite

Cell cycle and cell death after DNA damage

Journal Article FASEB JOURNAL · July 31, 1997 Link to item Cite

Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation.

Journal Article Nature · May 29, 1997 Ataxia telangiectasia (AT) is a rare human autosomal recessive disorder with pleiotropic phenotypes, including neuronal degeneration, immune dysfunction, premature ageing and increased cancer risk. The gene mutated in AT, ATM, encodes a putative lipid or p ... Full text Link to item Cite

Apoptosis in haematological malignancies.

Journal Article J Clin Pathol · May 1997 Full text Link to item Cite

Fragments of ATM which have dominant-negative or complementing activity.

Journal Article Mol Cell Biol · April 1997 The ATM protein has been implicated in pathways controlling cell cycle checkpoints, radiosensitivity, genetic instability, and aging. Expression of ATM fragments containing a leucine zipper motif in a human tumor cell line abrogated the S-phase checkpoint ... Full text Link to item Cite

Genetic instability and tumorigenesis: introduction.

Journal Article Curr Top Microbiol Immunol · 1997 Full text Link to item Cite

p53 and ATM: cell cycle, cell death, and cancer.

Journal Article Adv Cancer Res · 1997 The development of a normal cell into a tumor cell appears to depend in part on mutations in genes that normally control cell cycle and cell death, thereby resulting in inappropriate cellular survival and tumorigenesis. ATM ("mutated in ataxia-telangiectas ... Full text Link to item Cite

Role of p53 in apoptosis.

Journal Article Adv Pharmacol · 1997 Full text Link to item Cite

Chromosome end-to-end associations and telomerase activity during cancer progression in human cells after treatment with alpha-particles simulating radon progeny.

Journal Article Oncogene · October 3, 1996 Chromosome end-to-end associations seen at metaphase involve telomeres and are commonly observed in cells derived from individuals with ataxia telangiectasia and most types of human tumors. The associations may arise because of short telomeres and/or alter ... Link to item Cite

Human CD34+ hematopoietic progenitors have low, cytokine-unresponsive O6-alkylguanine-DNA alkyltransferase and are sensitive to O6-benzylguanine plus BCNU.

Journal Article Blood · September 1, 1996 Human bone marrow (BM) cells contain low levels of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, which may explain their susceptibility to nitrosourea-induced cytotoxicity and the development of secondary leukemia after nitrosourea treatmen ... Link to item Cite

Separate pathways for p53 induction by ionizing radiation and N-(phosphonoacetyl)-L-aspartate.

Journal Article Cancer Res · August 15, 1996 The tumor suppressor gene product, p53, appears to be a significant participant in signaling pathways that mediate cellular responses to cytotoxic stresses. In particular, p53 appears to be a critical determinant of whether the cell lives or dies and how i ... Link to item Cite

Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor.

Journal Article Nature · August 8, 1996 The E2A-HLF (for hepatic leukaemia factor) fusion gene, formed by action of the t(17;19) (q22;p13) chromosomal translocation, drives the leukaemic transformation of early B-cell precursors, but the mechanism of this activity remains unknown. Here we report ... Full text Link to item Cite

Signalling to p53: where does it all start?

Journal Article Bioessays · August 1996 Alterations in the p53 gene product appear to be a major factor in human tumorigenesis and may influence the responses of many human tumors to therapy. Much effort has focused on understanding the signals which normally initiate p53 growth-suppressive func ... Full text Link to item Cite

The p53 signal transduction pathway is intact in human neuroblastoma despite cytoplasmic localization.

Journal Article Am J Pathol · May 1996 Mutations of the p53 tumor suppressor gene are rarely found in neuroblastoma. Though typically a nuclear protein, a number of tumor cell types have recently been reported to exhibit cytoplasmic p53 immunostaining, and it has been suggested that altered cel ... Link to item Cite

The production and characterization of murine monoclonal antibodies to human Gadd45 raised against a recombinant protein.

Journal Article Hybridoma · August 1995 The production of two different murine monoclonal antibodies to human Gadd45, a protein that is induced in response to DNA damage, is reported. Antibodies were generated in a SJL mouse using a recombinant form of the human Gadd45 protein. Monoclonal antibo ... Full text Link to item Cite

Similarity of the DNA-damage responsiveness and growth-suppressive properties of waf1/cip1 and gadd45.

Journal Article Int J Oncol · May 1995 The cellular responses to genotoxic stress are complex involving both p53-dependent and independent mechanisms. In the case of the GADD genes, many stresses eliciting growth arrest have been shown to induce these genes in a coordinate fashion regardless of ... Full text Link to item Cite

Growth factor modulation of p53-mediated growth arrest versus apoptosis.

Journal Article Genes Dev · March 1, 1995 Irradiation of mammalian cells can cause cell cycle perturbations and apoptotic cell death. We have investigated the modulation of these physiologic end points by growth factor stimulation: irradiation of a murine hematopoietic cell line in the presence of ... Full text Link to item Cite

P53, cell cycle control and apoptosis: implications for cancer.

Journal Article Cancer Metastasis Rev · March 1995 Cellular proliferation depends on the rates of both cell division and cell death. Tumors frequently have decreased cell death as a primary mode of increased cell proliferation. Genetic changes resulting in loss of programmed cell death (apoptosis) are like ... Full text Link to item Cite

Induction of apoptosis by tumor suppressor genes and oncogenes.

Journal Article Semin Cancer Biol · February 1995 The p53 tumor suppressor gene product, and the bcr-abl, bcl-2, and c-myc gene products all appear to influence the susceptibility of cells to apoptosis. In addition to the role p53 protein plays in mediating a cell cycle arrest in G1 following DNA damage, ... Full text Link to item Cite

Characterization of human Gadd45, a p53-regulated protein.

Journal Article J Biol Chem · December 23, 1994 GADD45 (growth arrest and DNA damage) is a DNA-damage-inducible gene regulated in part by the tumor suppressor p53. A role in negative growth control has recently been suggested based on significant (more than 75%) reduction of colony formation following o ... Link to item Cite

Cell cycle control and cancer.

Journal Article Science · December 16, 1994 Multiple genetic changes occur during the evolution of normal cells into cancer cells. This evolution is facilitated in cancer cells by loss of fidelity in the processes that replicate, repair, and segregate the genome. Recent advances in our understanding ... Full text Link to item Cite

Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen.

Journal Article Science · November 25, 1994 GADD45 is a ubiquitously expressed mammalian gene that is induced by DNA damage and certain other stresses. Like another p53-regulated gene, p21WAF1/CIP1, whose product binds to cyclin-dependent kinases (Cdk's) and proliferating cell nuclear antigen (PCNA) ... Full text Link to item Cite

The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia.

Journal Article Cancer Res · October 1, 1994 The p53 protein is a critical participant in a signal transduction pathway which mediates a G1 cell cycle arrest and apoptotic cell death in mammalian cells after ionizing irradiation. Cells from patients with the cancer-prone, radiation-sensitive disorder ... Link to item Cite

p53-dependent G1 arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoprotein.

Journal Article Proc Natl Acad Sci U S A · June 7, 1994 The cell cycle regulatory tumor suppressor proteins p53 and pRB are targeted for inactivation by several tumor viruses, including the high-risk types of human papillomaviruses (HPVs) via interactions of the HPV E6 and E7 oncoproteins with p53 and pRB, resp ... Full text Link to item Cite

The p53-dependent gamma-ray response of GADD45.

Journal Article Cancer Res · May 15, 1994 Activation of the human GADD45 gene by ionizing radiation (IR) has previously been shown to be dependent on the tumor suppressor and transcription factor p53 (M. B. Kastan, et al., Cell 71: 587-597, 1992). Unlike GADD45, the response of other DNA damage-in ... Link to item Cite

Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway.

Journal Article Proc Natl Acad Sci U S A · March 29, 1994 Normal p53 function is required for optimal arrest of cells in the G1 phase of the cell cycle following certain types of DNA damage. Loss of this cell cycle checkpoint may contribute to tumor development by increasing the number of genetic abnormalities in ... Full text Link to item Cite

DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways.

Journal Article Mol Cell Biol · March 1994 The tumor suppressor protein p53 serves as a critical regulator of a G1 cell cycle checkpoint and of apoptosis following exposure of cells to DNA-damaging agents. The mechanism by which DNA-damaging agents elevate p53 protein levels to trigger G1/S arrest ... Full text Link to item Cite

WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis.

Journal Article Cancer Res · March 1, 1994 The tumor growth suppressor WAF1/CIP1 was recently shown to be induced by p53 and to be a potent inhibitor of cyclin-dependent kinases. In the present studies, we sought to determine the relationship between the expression of WAF1/CIP1 and endogenous regul ... Link to item Cite

P53 AND OTHER MOLECULAR CONTROLS OF THE RESPONSE TO DNA-DAMAGE

Journal Article JOURNAL OF CELLULAR BIOCHEMISTRY · February 13, 1994 Link to item Cite

P53 AND OTHER MOLECULAR CONTROLS OF THE RESPONSE TO DNA-DAMAGE

Journal Article JOURNAL OF CELLULAR BIOCHEMISTRY · February 13, 1994 Link to item Cite

Control of G1 arrest after DNA damage.

Journal Article Environ Health Perspect · December 1993 The temporal relationship between DNA damage and DNA replication may be critical in determining whether the genetic changes necessary for cellular transformation occur after DNA damage. Recent characterization of the mechanisms responsible for alterations ... Full text Link to item Cite

Discussion of Dr. Kastan's presentation

Journal Article Advances in Experimental Medicine and Biology · December 1, 1993 Cite

Experimental models of human carcinogenesis.

Journal Article Nat Genet · November 1993 Full text Link to item Cite

Loss of a p53-associated G1 checkpoint does not decrease cell survival following DNA damage.

Journal Article Cancer Res · September 15, 1993 Cell cycle checkpoints regulate progression through the cell cycle. In yeast, loss of the G2 checkpoint by mutation of the rad9 gene results in increased genetic instability as well as increased sensitivity to ionizing radiation. In contrast, comparing clo ... Link to item Cite

Altered cytoplasmic/nuclear distribution of the c-myc protein in differentiating ML-1 human myeloid leukemia cells.

Journal Article Cell Growth Differ · May 1993 The c-myc gene is thought to play a role in cell proliferation and differentiation; for example, constitutive expression of an exogenously introduced c-myc gene can inhibit differentiation in hematopoietic cell lines. Expression of the endogenous c-myc gen ... Link to item Cite

Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage.

Journal Article Proc Natl Acad Sci U S A · May 1, 1993 Infection with certain types of human papillomaviruses (HPV) is highly associated with carcinomas of the human uterine cervix. However, HPV infection alone does not appear to be sufficient for the process of malignant transformation, suggesting the require ... Full text Link to item Cite

Acute neurotoxicity after intrathecal cytosine arabinoside in two adolescents with acute lymphoblastic leukemia of B-cell type.

Journal Article Cancer · January 1, 1993 BACKGROUND: Two adolescents with acute B-cell leukemia (Burkitt leukemia) had acute severe neurotoxicity after treatment with intrathecal (IT) cytosine arabinoside (AraC) at a dose of 50 mg/day for three consecutive days. RESULTS: A 16-year-old boy had a r ... Full text Link to item Cite

A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia.

Journal Article Cell · November 13, 1992 Cell cycle checkpoints can enhance cell survival and limit mutagenic events following DNA damage. Primary murine fibroblasts became deficient in a G1 checkpoint activated by ionizing radiation (IR) when both wild-type p53 alleles were disrupted. In additio ... Full text Link to item Cite

Wild-type p53 is a cell cycle checkpoint determinant following irradiation.

Journal Article Proc Natl Acad Sci U S A · August 15, 1992 Cell cycle checkpoints appear to contribute to an increase in cell survival and a decrease in abnormal heritable genetic changes following exposure to DNA damaging agents. Though several radiation-sensitive yeast mutants have been identified, little is kno ... Full text Link to item Cite

Participation of p53 protein in the cellular response to DNA damage.

Journal Article Cancer Res · December 1, 1991 The inhibition of replicative DNA synthesis that follows DNA damage may be critical for avoiding genetic lesions that could contribute to cellular transformation. Exposure of ML-1 myeloblastic leukemia cells to nonlethal doses of the DNA damaging agents, g ... Link to item Cite

Levels of p53 protein increase with maturation in human hematopoietic cells.

Journal Article Cancer Res · August 15, 1991 Transfection of the wild-type p53 gene into malignant cell lines usually results in an inhibition of proliferation. However, the physiological function of the endogenous p53 gene product has been difficult to ascertain. In order to examine whether p53 is i ... Link to item Cite

Topoisomerase II levels during granulocytic maturation in vitro and in vivo.

Journal Article Cancer Res · July 1, 1991 Western blotting, indirect immunolocalization, flow cytometry, and a functional assay for drug-induced strand breakage were utilized to examine topoisomerase (topo) II levels during granulocytic maturation in HL-60 human progranulocytic leukemia cells and ... Link to item Cite

Normal human bone marrow precursors that express terminal deoxynucleotidyl transferase include T-cell precursors and possible lymphoid stem cells.

Journal Article Blood · April 15, 1991 To compare the differentiation of early B- and T-lymphoid precursors, we have used immune adherence combined with analytical flow cytometric techniques to enrich and characterize subsets of the small population of bone marrow mononuclear cells that express ... Link to item Cite

Participation of p53 Protein in the Cellular Response to DNA Damage

Journal Article Cancer Research · January 1, 1991 The inhibition of replicative DNA synthesis that follows DNA damage may be critical for avoiding genetic lesions that could contribute to cellular transformation. Exposure of MI -1 myeloblastic leukemia cells to nonlethal doses of the DNA damaging agents, ... Cite

Detection of minimal residual T cell acute lymphoblastic leukemia by flow cytometry.

Journal Article J Immunol Methods · September 14, 1990 We have developed a flow cytometric assay for the determination of cellular expression of terminal deoxynucleotidyl transferase (TdT) and applied this to the detection of minimal residual T cell acute lymphoblastic leukemia (T-ALL). The flow cytometric ass ... Full text Link to item Cite

Flow cytometric identification of intracellular antigens: detection of minimal residual leukemia.

Journal Article Bone Marrow Transplant · July 1990 Recent advances in preparation of cells for flow cytometric analysis have enabled the sensitive detection of intracellular antigens. We have examined the utility of two color flow cytometry for the detection of minimal residual T cell acute lymphoblastic l ... Link to item Cite

Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells.

Journal Article Blood · May 15, 1990 Relative levels of cytoplasmic aldehyde dehydrogenase (ALDH) were determined in selected subpopulations of normal human bone marrow cells using a flow cytometric assay that simultaneously detects a cell surface antigen (as a marker of cell lineage and deve ... Link to item Cite

Acute leukemia in children.

Journal Article Curr Opin Oncol · February 1990 Full text Link to item Cite

Nuclear oncoprotein expression as a function of lineage, differentiation stage, and proliferative status of normal human hematopoietic cells.

Journal Article Blood · October 1989 Relative levels of the nuclear oncoproteins c-myb, c-myc, and c-fos were determined in selected subpopulations of normal human bone marrow (BM) cells using a flow cytometric assay which simultaneously detects a cell-surface antigen (as a marker of lineage ... Link to item Cite

Expression of protooncogene c-myb in normal human hematopoietic cells.

Journal Article Blood · May 1, 1989 Expression of the protooncogene, c-myb, in various subpopulations of normal human hematopoietic cells was characterized. Cells expressing the immature cell surface marker, CD34 (My10), were isolated by immune adherence with the "panning" technique or immun ... Link to item Cite

Philadelphia-chromosome positive essential thrombocythemia. Two cases in children.

Journal Article Am J Pediatr Hematol Oncol · 1989 Two cases of children with essential thrombocythemia (ET) with the presence of a Philadelphia chromosome (Ph1) are presented and discussed. Diagnosis was based on their clinical presentation and marked primary thrombocytosis. The site of the Ph1 translocat ... Link to item Cite

The role of hematopoietic growth factors and oncogenes in leukemogenesis.

Journal Article Am J Pediatr Hematol Oncol · 1989 Understanding of the roles and molecular mechanisms of hematopoietic growth factors has increased greatly in recent years. This past decade has also brought us tantalizingly close to linking a group of genes normally involved in the regulation of growth an ... Link to item Cite

Distribution of 5-methyldeoxycytidine in products of staphylococcal nuclease digestion of nuclei and purified DNA.

Journal Article Biochemistry · March 12, 1985 We have compared the distribution of 5-methyldeoxycytidine (m5dC) between staphylococcal nuclease (SN) sensitive and resistant regions of human diploid fibroblast chromatin to the corresponding distribution in purified DNA. After SN digestion of fibroblast ... Full text Link to item Cite

METHYLATION OF DEOXYCYTIDINE INCORPORATED BY REPAIR SYNTHESIS FOLLOWING DAMAGE WITH ULTRAVIOLET-RADIATION AND CHEMICAL CARCINOGENS

Journal Article PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH · January 1, 1983 Link to item Cite

Methylation of deoxycytidine incorporated by excision-repair synthesis of DNA.

Journal Article Cell · September 1982 Methylation of deoxycytidine incorporated by DNA excision-repair was studied in human diploid fibroblasts following damage with ultraviolet radiation, N-methyl-N-nitrosourea, or N-acetoxy-2-acetylaminofluorene. In confluent, nondividing cells, methylation ... Full text Link to item Cite