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Christopher M. Counter

George Barth Geller Distinguished Professor of Pharmacology
Pharmacology & Cancer Biology

Selected Publications


p53 dosage can impede KrasG12D- and KrasQ61R-mediated tumorigenesis.

Journal Article PLoS One · 2024 Mice engineered with a G12D versus Q61R mutation in Kras exhibited differences in tumorigenesis. Namely, the incidence or grade of oral or forestomach squamous epithelial lesions was more prevalent in the KrasG12D background while hematolymphopoietic disea ... Full text Link to item Cite

Abstract LB263: An in vivo unbiased screen identifies clathrin adaptor protein complex-2 as a novel tumor suppressor

Conference Cancer Research · April 14, 2023 AbstractPancreatic ductal adenocarcinoma (PDAC) is almost uniformly lethal. It is thus imperative to find new therapeutic approaches to treat this disease. While whole genome CRISPR/Cas9 screens have success ... Full text Cite

Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis.

Journal Article Elife · September 7, 2022 Despite multiple possible oncogenic mutations in the proto-oncogene KRAS, unique subsets of these mutations are detected in different cancer types. As KRAS mutations occur early, if not being the initiating event, these mutational biases are ostensibly a p ... Full text Link to item Cite

Distinct responses to rare codons in select Drosophila tissues.

Journal Article Elife · May 6, 2022 Codon usage bias has long been appreciated to influence protein production. Yet, relatively few studies have analyzed the impacts of codon usage on tissue-specific mRNA and protein expression. Here, we use codon-modified reporters to perform an organism-wi ... Full text Link to item Cite

Non-canonical genomic driver mutations of urethane carcinogenesis.

Journal Article PLoS One · 2022 The carcinogen urethane induces pulmonary tumors in mice initiated by an incredibly specific Q61L/R oncogenic mutation in the proto-oncogene Kras. Previous Whole-Exome Sequencing of urethane-induced tumors revealed a bias towards A➙T/G and G➙A substitution ... Full text Link to item Cite

An ultra-sensitive method to detect mutations in human RAS templates.

Journal Article Small GTPases · January 2022 The RAS family of small GTPases is mutated in roughly a fifth of human cancers. Hotspot point mutations at codons G12, G13, and Q61 account for 95% of all these mutations, which are well established to render the encoded proteins oncogenic. In humans, this ... Full text Link to item Cite

CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment.

Journal Article Cell Rep · November 30, 2021 We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alo ... Full text Link to item Cite

Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.

Journal Article Nat Commun · September 9, 2021 The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate ho ... Full text Link to item Cite

Signaling levels mold the RAS mutation tropism of urethane.

Journal Article Elife · May 17, 2021 RAS genes are commonly mutated in human cancer. Despite many possible mutations, individual cancer types often have a 'tropism' towards a specific subset of RAS mutations. As driver mutations, these patterns ostensibly originate from normal cells. High onc ... Full text Link to item Cite

Using BioID to Characterize the RAS Interactome.

Journal Article Methods Mol Biol · 2021 Identifying the proteins that associate with RAS oncoproteins has great potential, not only to elucidate how these mutant proteins are regulated and signal but also to identify potential therapeutic targets. Here we describe a detailed protocol to employ p ... Full text Link to item Cite

RAS mutation patterns arise from tissue-specific responses to distinct oncogenic signaling

Journal Article · 2021 Despite multiple possible oncogenic mutations in the proto-oncogene KRAS , unique subsets of these mutations are detected in different cancer types. As KRAS mutations occur early, if not being initiating, these mutational biases are ostensibly a product of ... Full text Cite

Expression of transgenes enriched in rare codons is enhanced by the MAPK pathway.

Journal Article Sci Rep · December 17, 2020 The ability to translate three nucleotide sequences, or codons, into amino acids to form proteins is conserved across all organisms. All but two amino acids have multiple codons, and the frequency that such synonymous codons occur in genomes ranges from ra ... Full text Link to item Cite

Exploiting codon usage identifies intensity-specific modifiers of Ras/MAPK signaling in vivo.

Journal Article PLoS Genet · December 2020 Signal transduction pathways are intricately fine-tuned to accomplish diverse biological processes. An example is the conserved Ras/mitogen-activated-protein-kinase (MAPK) pathway, which exhibits context-dependent signaling output dynamics and regulation. ... Full text Link to item Cite

Capturing the primordial Kras mutation initiating urethane carcinogenesis.

Journal Article Nat Commun · April 14, 2020 The environmental carcinogen urethane exhibits a profound specificity for pulmonary tumors driven by an oncogenic Q61L/R mutation in the gene Kras. Similarly, the frequency, isoform, position, and substitution of oncogenic RAS mutations are often unique to ... Full text Link to item Cite

Exploiting codon usage identifies RpS21 as an in vivo signal strength-dependent Ras/MAPK regulator

Journal Article · May 26, 2019 ABSTRACT Signal transduction pathways are intricately fine-tuned to accomplish diverse biological processes. An example is the conserved Ras/mitogen-activated-protein-kinase (MAPK) pathway, which exhibits context-dependent signaling output dynamics and reg ... Full text Cite

A model for RAS mutation patterns in cancers: finding the sweet spot.

Journal Article Nat Rev Cancer · December 2018 The three RAS genes - HRAS, NRAS and KRAS - are collectively mutated in one-third of human cancers, where they act as prototypic oncogenes. Interestingly, there are rather distinct patterns to RAS mutations; the isoform mutated as well as the position and ... Full text Link to item Cite

Codon usage regulates human KRAS expression at both transcriptional and translational levels.

Journal Article J Biol Chem · November 16, 2018 KRAS and HRAS are highly homologous oncogenic Ras GTPase family members that are mutated in a wide spectrum of human cancers. Despite having high amino acid identity, KRAS and HRAS have very different codon usage biases: the HRAS gene contains many common ... Full text Link to item Cite

Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.

Journal Article Nat Commun · September 7, 2018 In human cancers, oncogenic mutations commonly occur in the RAS genes KRAS, NRAS, or HRAS, but there are no clinical RAS inhibitors. Mutations are more prevalent in KRAS, possibly suggesting a unique oncogenic activity mediated by KRAS-specific interaction ... Full text Link to item Cite

p53 dosage can impede KrasG12D- and KrasQ61R-mediated tumorigenesis.

Journal Article PLoS One · 2024 Mice engineered with a G12D versus Q61R mutation in Kras exhibited differences in tumorigenesis. Namely, the incidence or grade of oral or forestomach squamous epithelial lesions was more prevalent in the KrasG12D background while hematolymphopoietic disea ... Full text Link to item Cite

Abstract LB263: An in vivo unbiased screen identifies clathrin adaptor protein complex-2 as a novel tumor suppressor

Conference Cancer Research · April 14, 2023 AbstractPancreatic ductal adenocarcinoma (PDAC) is almost uniformly lethal. It is thus imperative to find new therapeutic approaches to treat this disease. While whole genome CRISPR/Cas9 screens have success ... Full text Cite

Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis.

Journal Article Elife · September 7, 2022 Despite multiple possible oncogenic mutations in the proto-oncogene KRAS, unique subsets of these mutations are detected in different cancer types. As KRAS mutations occur early, if not being the initiating event, these mutational biases are ostensibly a p ... Full text Link to item Cite

Distinct responses to rare codons in select Drosophila tissues.

Journal Article Elife · May 6, 2022 Codon usage bias has long been appreciated to influence protein production. Yet, relatively few studies have analyzed the impacts of codon usage on tissue-specific mRNA and protein expression. Here, we use codon-modified reporters to perform an organism-wi ... Full text Link to item Cite

Non-canonical genomic driver mutations of urethane carcinogenesis.

Journal Article PLoS One · 2022 The carcinogen urethane induces pulmonary tumors in mice initiated by an incredibly specific Q61L/R oncogenic mutation in the proto-oncogene Kras. Previous Whole-Exome Sequencing of urethane-induced tumors revealed a bias towards A➙T/G and G➙A substitution ... Full text Link to item Cite

An ultra-sensitive method to detect mutations in human RAS templates.

Journal Article Small GTPases · January 2022 The RAS family of small GTPases is mutated in roughly a fifth of human cancers. Hotspot point mutations at codons G12, G13, and Q61 account for 95% of all these mutations, which are well established to render the encoded proteins oncogenic. In humans, this ... Full text Link to item Cite

CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment.

Journal Article Cell Rep · November 30, 2021 We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alo ... Full text Link to item Cite

Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.

Journal Article Nat Commun · September 9, 2021 The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate ho ... Full text Link to item Cite

Signaling levels mold the RAS mutation tropism of urethane.

Journal Article Elife · May 17, 2021 RAS genes are commonly mutated in human cancer. Despite many possible mutations, individual cancer types often have a 'tropism' towards a specific subset of RAS mutations. As driver mutations, these patterns ostensibly originate from normal cells. High onc ... Full text Link to item Cite

Using BioID to Characterize the RAS Interactome.

Journal Article Methods Mol Biol · 2021 Identifying the proteins that associate with RAS oncoproteins has great potential, not only to elucidate how these mutant proteins are regulated and signal but also to identify potential therapeutic targets. Here we describe a detailed protocol to employ p ... Full text Link to item Cite

RAS mutation patterns arise from tissue-specific responses to distinct oncogenic signaling

Journal Article · 2021 Despite multiple possible oncogenic mutations in the proto-oncogene KRAS , unique subsets of these mutations are detected in different cancer types. As KRAS mutations occur early, if not being initiating, these mutational biases are ostensibly a product of ... Full text Cite

Expression of transgenes enriched in rare codons is enhanced by the MAPK pathway.

Journal Article Sci Rep · December 17, 2020 The ability to translate three nucleotide sequences, or codons, into amino acids to form proteins is conserved across all organisms. All but two amino acids have multiple codons, and the frequency that such synonymous codons occur in genomes ranges from ra ... Full text Link to item Cite

Exploiting codon usage identifies intensity-specific modifiers of Ras/MAPK signaling in vivo.

Journal Article PLoS Genet · December 2020 Signal transduction pathways are intricately fine-tuned to accomplish diverse biological processes. An example is the conserved Ras/mitogen-activated-protein-kinase (MAPK) pathway, which exhibits context-dependent signaling output dynamics and regulation. ... Full text Link to item Cite

Capturing the primordial Kras mutation initiating urethane carcinogenesis.

Journal Article Nat Commun · April 14, 2020 The environmental carcinogen urethane exhibits a profound specificity for pulmonary tumors driven by an oncogenic Q61L/R mutation in the gene Kras. Similarly, the frequency, isoform, position, and substitution of oncogenic RAS mutations are often unique to ... Full text Link to item Cite

Exploiting codon usage identifies RpS21 as an in vivo signal strength-dependent Ras/MAPK regulator

Journal Article · May 26, 2019 ABSTRACT Signal transduction pathways are intricately fine-tuned to accomplish diverse biological processes. An example is the conserved Ras/mitogen-activated-protein-kinase (MAPK) pathway, which exhibits context-dependent signaling output dynamics and reg ... Full text Cite

A model for RAS mutation patterns in cancers: finding the sweet spot.

Journal Article Nat Rev Cancer · December 2018 The three RAS genes - HRAS, NRAS and KRAS - are collectively mutated in one-third of human cancers, where they act as prototypic oncogenes. Interestingly, there are rather distinct patterns to RAS mutations; the isoform mutated as well as the position and ... Full text Link to item Cite

Codon usage regulates human KRAS expression at both transcriptional and translational levels.

Journal Article J Biol Chem · November 16, 2018 KRAS and HRAS are highly homologous oncogenic Ras GTPase family members that are mutated in a wide spectrum of human cancers. Despite having high amino acid identity, KRAS and HRAS have very different codon usage biases: the HRAS gene contains many common ... Full text Link to item Cite

Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.

Journal Article Nat Commun · September 7, 2018 In human cancers, oncogenic mutations commonly occur in the RAS genes KRAS, NRAS, or HRAS, but there are no clinical RAS inhibitors. Mutations are more prevalent in KRAS, possibly suggesting a unique oncogenic activity mediated by KRAS-specific interaction ... Full text Link to item Cite

Copper Chelation as Targeted Therapy in a Mouse Model of Oncogenic BRAF-Driven Papillary Thyroid Cancer.

Journal Article Clin Cancer Res · September 1, 2018 Purpose: Sixty percent of papillary thyroid cancers (PTC) have an oncogenic (V600E) BRAF mutation. Inhibitors of BRAF and its substrates MEK1/2 are showing clinical promise in BRAFV600E PTC. PTC progression can be decades long, which is challenging in term ... Full text Link to item Cite

Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells.

Journal Article J Clin Invest · August 31, 2018 Intestinal homeostasis depends on a slowly proliferating stem cell compartment in crypt cells, followed by rapid proliferation of committed progenitor cells in the transit amplifying (TA) compartment. The balance between proliferation and differentiation i ... Full text Link to item Cite

Wild-type Kras expands and exhausts hematopoietic stem cells.

Journal Article JCI Insight · June 7, 2018 Oncogenic Kras expression specifically in hematopoietic stem cells (HSCs) induces a rapidly fatal myeloproliferative neoplasm in mice, suggesting that Kras signaling plays a dominant role in normal hematopoiesis. However, such a conclusion is based on expr ... Full text Link to item Cite

Copper Chelation Inhibits BRAFV600E-Driven Melanomagenesis and Counters Resistance to BRAFV600E and MEK1/2 Inhibitors.

Journal Article Cancer Res · November 15, 2017 MEK1/2 and BRAFV600E inhibitors are used to treat BRAFV600E-positive melanoma, with other cancers under evaluation. Genetic perturbation of copper import or pharmacologic reduction of copper with the clinical copper chelator TTM inhibits MEK1/2 kinase acti ... Full text Link to item Cite

A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution.

Journal Article Cell Rep · July 25, 2017 Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematical ... Full text Link to item Cite

Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance.

Journal Article Nat Commun · June 8, 2017 KRAS mutations drive resistance to targeted therapies, including EGFR inhibitors in colorectal cancer (CRC). Through genetic screens, we unexpectedly find that mutant HRAS, which is rarely found in CRC, is a stronger driver of resistance than mutant KRAS. ... Full text Link to item Cite

Treatment with the nitric oxide synthase inhibitor L-NAME provides a survival advantage in a mouse model of Kras mutation-positive, non-small cell lung cancer.

Journal Article Oncotarget · July 5, 2016 Oncogenic mutations in the gene KRAS are commonly detected in non-small cell lung cancer (NSCLC). This disease is inherently difficult to treat, and combinations involving platinum-based drugs remain the therapeutic mainstay. In terms of novel, pharmacolog ... Full text Link to item Cite

Isoform-Specific Effects of Wild-Type Ras Genes on Carcinogen-Induced Lung Tumorigenesis in Mice.

Journal Article PLoS One · 2016 The gene KRAS is commonly mutated in lung cancer to encode a constitutively active and oncogenic protein that is well established to initiate and maintain lung tumorigenesis. However, the remaining wild-type KRAS protein, or the other family members HRAS a ... Full text Link to item Cite

Evaluating The Role Of Nitric Oxide Synthase In Oncogenic Ras-Driven Tumorigenesis.

Journal Article Redox Biol · August 2015 We previously reported that oncogenic KRAS activation of the PI3K/AKT pathway stimulates the remaining wild-type HRAS and NRAS proteins in a manner dependent upon both eNOS expression and C118 in HRAS and NRAS, which promoted tumor growth. Interestingly ho ... Full text Link to item Cite

Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth.

Journal Article Mol Cell · February 5, 2015 Ras is mutated in up to 30% of cancers, including 90% of pancreatic ductal adenocarcinomas, causing it to be constitutively GTP-bound, and leading to activation of downstream effectors that promote a tumorigenic phenotype. As targeting Ras directly is diff ... Full text Link to item Cite

Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer.

Journal Article PLoS One · 2015 Oncogenic, activating mutations in KRAS initiate pancreatic cancer. There are, however, two other Ras family members, Nras and Hras, which can be activated in the presence of oncogenic Kras. The role of these wild-type Ras proteins in cancer remains unclea ... Full text Link to item Cite

cPLA2 regulates the expression of type I interferons and intracellular immunity to Chlamydia trachomatis.

Journal Article J Biol Chem · July 9, 2010 Infection with the obligate bacterial intracellular pathogen Chlamydia trachomatis leads to the sustained activation of the small GTPase RAS and many of its downstream signaling components. In particular, the mitogen-activated protein kinase ERK and the ca ... Full text Link to item Cite

Sec5 and Exo84 foster oncogenic ras-mediated tumorigenesis.

Journal Article Mol Cancer Res · February 2010 The genes encoding the Ras family of small GTPases are mutated to yield constitutively active GTP-bound oncogenic proteins in one third of all human cancers. Oncogenic Ras binds to and activates a number of proteins that promote tumorigenic phenotypes, inc ... Full text Link to item Cite

Utility of telomerase-pot1 fusion protein in vascular tissue engineering.

Journal Article Cell Transplant · 2010 While advances in regenerative medicine and vascular tissue engineering have been substantial in recent years, important stumbling blocks remain. In particular, the limited life span of differentiated cells that are harvested from elderly human donors is a ... Full text Open Access Link to item Cite

Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA.

Journal Article Mol Cell Biol · January 2010 The small GTPase Ras, which transmits extracellular signals to the cell, and the kinase Aurora-A, which promotes proper mitosis, can both be inappropriately activated in human tumors. Here, we show that Aurora-A in conjunction with oncogenic Ras enhances t ... Full text Link to item Cite

ELR+ CXC chemokines and oncogenic Ras-mediated tumorigenesis.

Journal Article Carcinogenesis · November 2009 The small GTPase Ras is mutated to remain in the active oncogenic state in one-third of human cancers, thereby promoting tumorigenesis. It has recently come to light that one consequence of oncogenic Ras signaling is secretion of cytokines vascular endothe ... Full text Link to item Cite

POT1 association with TRF2 regulates telomere length.

Journal Article Mol Cell Biol · October 2009 Deleting the OB folds encoding the telomeric single-stranded DNA (ssDNA)-binding activity of the human telomeric protein POT1 induces significant telomere elongation, suggesting that at least one critical aspect of the regulation of telomere length is disr ... Full text Link to item Cite

Defining the cooperative genetic changes that temporally drive alveolar rhabdomyosarcoma.

Journal Article Cancer Res · December 1, 2008 Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with a histologic variant of RMS known as alveolar (aRMS) have a 5-year survival rate of <30%. aRMS tissues exhibit a number o ... Full text Link to item Cite

The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis.

Journal Article Cancer Res · September 15, 2008 Histone deacetylase inhibitors (HDACI) are promising antitumor agents. Although transcriptional deregulation is thought to be the main mechanism underlying their therapeutic effects, the exact mechanism and targets by which HDACIs achieve their antitumor e ... Full text Link to item Cite

Telomerase reverse transcriptase is required for the localization of telomerase RNA to cajal bodies and telomeres in human cancer cells.

Journal Article Mol Biol Cell · September 2008 Telomere maintenance by telomerase is critical for the unlimited division potential of most human cancer cells. The two essential components of human telomerase, telomerase RNA (hTR) and telomerase reverse transcriptase (hTERT), are recruited from distinct ... Full text Link to item Cite

Distinct functions of POT1 at telomeres.

Journal Article Mol Cell Biol · September 2008 The mammalian protein POT1 binds to telomeric single-stranded DNA (ssDNA), protecting chromosome ends from being detected as sites of DNA damage. POT1 is composed of an N-terminal ssDNA-binding domain and a C-terminal protein interaction domain. With regar ... Full text Link to item Cite

The protein hSnm1B is stabilized when bound to the telomere-binding protein TRF2.

Journal Article J Biol Chem · August 29, 2008 hSnm1B is member of the SNM family of exonucleases involved in DNA processing and is known to be localized to telomeres via binding to the telomere-binding protein TRF2. Here we demonstrate that the C terminus of hSnm1B facilitates the concentration of hSn ... Full text Link to item Cite

Tumour maintenance is mediated by eNOS.

Journal Article Nature · April 3, 2008 Tumour cells become addicted to the expression of initiating oncogenes like Ras, such that loss of oncogene expression in established tumours leads to tumour regression. HRas, NRas or KRas are mutated to remain in the active GTP-bound oncogenic state in ma ... Full text Link to item Cite

Tethering telomeric double- and single-stranded DNA-binding proteins inhibits telomere elongation.

Journal Article J Biol Chem · March 14, 2008 Mammalian telomeres are composed of G-rich repetitive double-stranded (ds) DNA with a 3' single-stranded (ss) overhang and associated proteins that together maintain chromosome end stability. Complete replication of telomeric DNA requires de novo elongatio ... Full text Link to item Cite

Oncogenic ras-induced expression of cytokines: a new target of anti-cancer therapeutics.

Journal Article Mol Interv · February 2008 The Ras family of small guanosine triphosphatases normally transmit signals from cell surface receptors to the interior of the cell. Stimulation of cell surface receptors leads to the activation of guanine exchange factors, which, in turn, convert Ras from ... Full text Link to item Cite

Genetic modeling of Ras-induced human rhabdomyosarcoma.

Journal Article Methods Enzymol · 2008 Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Historically, rhabdomyosarcoma has been studied by the manipulation of human cell lines derived from primary rhabdomyosarcoma tumor tissue adapted to grow in culture. Rec ... Full text Link to item Cite

DNA-based animal models of human disease: from genotype to phenotype.

Journal Article Dev Biol (Basel) · 2008 Biomedical research utilizes animal models to elucidate human disease processes at the cellular and molecular level and for the development of new therapies. Traditionally, mammalian models have been limited to the mouse, primarily because of well characte ... Full text Link to item Cite

A method to generate genetically defined tumors in pigs.

Journal Article Methods Enzymol · 2008 As a biomedical model, pigs offer many advantages and hence have been utilized extensively for toxicology, Crohn's disease, diabetes, and organ transplantation, as well as many other research areas. However, the advantages of porcine models, particularly i ... Full text Link to item Cite

Characterization of the porcine ATM gene: towards the generation of a novel non-murine animal model for Ataxia-Telangiectasia.

Journal Article Gene · December 15, 2007 Ataxia-Telangiectasia (A-T) is a genetic disorder causing cerebellar degeneration, immune deficiency, cancer predisposition, chromosomal instability and radiation sensitivity. Among the mutations responsible for A-T, 85% represent truncating mutations that ... Full text Link to item Cite

From bread to bedside: What budding yeast has taught us about the immortalization of cancer cells

Journal Article · December 1, 2007 The budding yeast Saccharomyces cerevisiae is a formidable model system indeed. With the entire genome sequenced, unparalleled genetic malleability, and an eukaryotic background, this system is virtually beyond compare for studying the multitude of biologi ... Full text Cite

Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis.

Journal Article Genes Dev · July 15, 2007 Ras is mutated to remain in the active oncogenic state in many cancers. As Ras has proven difficult to target therapeutically, we searched for secreted, druggable proteins induced by Ras that are required for tumorigenesis. We found that Ras induces the se ... Full text Link to item Cite

The PAX3-FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence.

Journal Article Cancer Res · July 15, 2007 Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with a histologic variant of rhabdomyosarcoma known as alveolar rhabdomyosarcoma (ARMS) have a 5-year survival of <30%. ARMS is char ... Full text Link to item Cite

Genetic modeling of alveolar rhabdomyosarcoma

Journal Article PEDIATRIC BLOOD & CANCER · June 1, 2007 Link to item Cite

Genetic induction of tumorigenesis in swine.

Journal Article Oncogene · February 15, 2007 The transition from basic to clinical cancer research for a number of experimental therapeutics is hampered by the lack of a genetically malleable, large animal model. To this end, we genetically engineered primary porcine cells to be tumorigenic by expres ... Full text Link to item Cite

Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells.

Journal Article Curr Biol · December 19, 2006 BACKGROUND: The Ral guanine nucleotide-exchange factors (RalGEFs) serve as key effectors for Ras oncogene transformation of immortalized human cells. RalGEFs are activators of the highly related RalA and RalB small GTPases, although only the former has bee ... Full text Link to item Cite

hSnm1B is a novel telomere-associated protein.

Journal Article J Biol Chem · June 2, 2006 Artemis, a member of the beta-CASP family, has been implicated in the regulation of both telomere stability and length. Prompted by this, we examined whether the other two putative DNA-binding members of this family, hSnm1A and hSnm1B, may associate with t ... Full text Link to item Cite

Genetically engineered human cancer models utilizing mammalian transgene expression.

Journal Article Cell Cycle · May 2006 Cancer models are vital to cancer biology research, and multiple cancer models are currently available that utilize either murine or human cells, each with particular strengths and weaknesses. The ability to transform primary human cells into tumors throug ... Full text Link to item Cite

A genetically defined normal human somatic cell system to study ras oncogenesis in vivo and in vitro.

Journal Article Methods Enzymol · 2006 Transgenic mice, cultured murine cells, and human cancer cell lines have widely been used to study Ras oncogenesis. Although extremely valuable systems, they could not be used to study Ras function in genetically defined human cells. In this regard, Ras is ... Full text Link to item Cite

Use of retrovirus expression of interfering RNA to determine the contribution of activated K-Ras and ras effector expression to human tumor cell growth.

Journal Article Methods Enzymol · 2006 Cancer is a multistep genetic process that includes mutational activation of oncogenes and inactivation of tumor suppressor genes. The Ras oncogenes are the most frequently mutated oncogenes in human cancers (30%), with a high frequency associated with can ... Full text Link to item Cite

Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance.

Journal Article Cancer Cell · November 2005 While tumors become addicted to oncogenes like Ras, the microenvironment in which tumor cells reside changes during tumorigenesis; the cells are surrounded initially by normal tissue and later by tumor tissue. Hence, we asked if Ras exerts its oncogenic ef ... Full text Link to item Cite

A network of genetic events sufficient to convert normal human cells to a tumorigenic state.

Journal Article Cancer Res · November 1, 2005 Although great progress has been made at identifying and characterizing individual genes involved in cancer, less is known about how the combination of such genes collaborate to form tumors in humans. To this end, we sought to genetically recreate tumorige ... Full text Link to item Cite

Blood vessels engineered from human cells.

Journal Article Lancet · September 10, 2005 Full text Link to item Cite

Blood vessels engineered from human cells.

Journal Article Lancet · June 18, 2005 Tissue engineering has made considerable progress in the past decade, but advances have stopped short of clinical application for most tissues. We postulated that an obstacle in engineering human tissues is the limited replicative capacity of adult somatic ... Full text Link to item Cite

Activation of RalA is critical for Ras-induced tumorigenesis of human cells.

Journal Article Cancer Cell · June 2005 RalGEFs were recently shown to be critical for Ras-mediated transformed and tumorigenic growth of human cells. We now show that the oncogenic activity of these proteins is propagated by activation of one RalGEF substrate, RalA, but blunted by another close ... Full text Link to item Cite

Genetic modeling of human rhabdomyosarcoma.

Journal Article Cancer Res · June 1, 2005 Rhabdomyosarcoma, a malignancy showing features of skeletal muscle differentiation, is the most common soft tissue sarcoma of childhood. The identification of distinct clinical presentation patterns, histologic tumor types, and risk groups suggests that rh ... Full text Link to item Cite

Loss of hPot1 function leads to telomere instability and a cut-like phenotype.

Journal Article Curr Biol · December 29, 2004 The human telomere binding protein hPot1 binds to the most distal single-stranded extension of telomeric DNA in vitro, and probably in vivo, as well as associating with the double-stranded telomeric DNA binding proteins TRF1 and TRF2 through the bridging p ... Full text Link to item Cite

Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR.

Journal Article J Biol Chem · December 10, 2004 The addition of telomeric repeats to chromosome ends by the enzyme telomerase is a highly orchestrated process. Although much is known regarding telomerase catalytic activity in vitro, less is known about how this activity is regulated in vivo to ensure pr ... Full text Link to item Cite

Genomics and clinical medicine: rationale for creating and effectively evaluating animal models.

Journal Article Exp Biol Med (Maywood) · October 2004 Because resolving human complex diseases is difficult, appropriate biomedical models must be developed and validated. In the past, researchers have studied diseases either by characterizing a human clinical disease and choosing the most appropriate animal ... Full text Link to item Cite

Leveling the playing field.

Journal Article Mol Cell · August 27, 2004 Using a genetically malleable model system that allows direct comparisons between human and mouse cells, Weinberg and colleagues lay to rest any doubt that murine cells are more easily transformed than human cells, and additionally, find that there may be ... Full text Link to item Cite

A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells.

Journal Article Nat Cell Biol · April 2004 The stability of c-Myc is regulated by multiple Ras effector pathways. Phosphorylation at Ser 62 stabilizes c-Myc, whereas subsequent phosphorylation at Thr 58 is required for its degradation. Here we show that Ser 62 is dephosphorylated by protein phospha ... Full text Link to item Cite

Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1.

Journal Article Mol Cell Biol · April 2004 The protein hPot1 shares homology with telomere-binding proteins in lower eukaryotes and associates with single-stranded telomeric DNA in vitro as well as colocalizing with telomere-binding proteins in vivo. We now show that hPot1 is coimmunoprecipitated w ... Full text Link to item Cite

Creating porcine biomedical models through recombineering.

Journal Article Comp Funct Genomics · 2004 Recent advances in genomics provide genetic information from humans and other mammals (mouse, rat, dog and primates) traditionally used as models as well as new candidates (pigs and cattle). In addition, linked enabling technologies, such as transgenesis a ... Full text Link to item Cite

In vivo regulation of hTERT expression and telomerase activity by androgen.

Journal Article J Urol · August 2003 PURPOSE: The most effective therapy for metastatic prostate cancer is androgen deprivation. Genes activated directly or possibly even indirectly by this steroid hormone represent potential targets for anticancer therapy. One such gene may be hTERT, which e ... Full text Link to item Cite

Human arteries engineered in vitro.

Journal Article EMBO Rep · June 2003 There is a pressing need to develop methods to engineer small-calibre arteries for bypass surgery. We hypothesized that the rate-limiting step that has thwarted previous attempts to engineer such vessels from non-neonatal tissues is the limited proliferati ... Full text Link to item Cite

Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model.

Journal Article J Biol Chem · May 2, 2003 We employed a genetically defined human cancer model to investigate the contributions of two genes up-regulated in several cancers to phenotypic changes associated with late stages of tumorigenesis. Specifically, tumor cells expressing two structurally unr ... Full text Link to item Cite

Putative telomere-recruiting domain in the catalytic subunit of human telomerase.

Journal Article Mol Cell Biol · May 2003 Telomerase, the enzyme that elongates telomeres, is essential to maintain telomere length and to immortalize most cancer cells. However, little is known about the regulation of this enzyme in higher eukaryotes. We previously described a domain in the hTERT ... Full text Link to item Cite

Telomere shortening in cultured autografts of patients with burns.

Journal Article Lancet · April 19, 2003 In extensive third-degree burns, donor sites for conventional split thickness skin grafts are limited. In such cases, cultured epithelial (keratinocyte) grafts are prepared from small samples of the patient's own skin and expanded in tissue culture, a proc ... Full text Link to item Cite

Mutational analysis defines a minimum level of telomerase activity required for tumourigenic growth of human cells.

Journal Article Oncogene · October 10, 2002 A hallmark of cancer cells is the ability to proliferate indefinitely. This acquisition of an immortal lifespan usually requires the activation of telomerase, the enzyme that elongates telomeres. Human telomerase is minimally composed of the reverse transc ... Full text Link to item Cite

C-terminal regions of the human telomerase catalytic subunit essential for in vivo enzyme activity.

Journal Article Mol Cell Biol · September 2002 Most human cancer cells are thought to acquire the ability to divide beyond the capacity of normal somatic cells through illegitimately activating the gene hTERT, which encodes the catalytic subunit of telomerase. While telomerase reverse transcriptase (TE ... Full text Link to item Cite

Distinct requirements for Ras oncogenesis in human versus mouse cells.

Journal Article Genes Dev · August 15, 2002 The spectrum of tumors associated with oncogenic Ras in humans often differs from those in mice either treated with carcinogens or engineered to sporadically express oncogenic Ras, suggesting that the mechanism of Ras transformation may be different in hum ... Full text Link to item Cite

The nucleolar localization domain of the catalytic subunit of human telomerase.

Journal Article J Biol Chem · July 5, 2002 Telomerase is the enzyme essential to complete the replication of the terminal DNA of most eukaryotic chromosomes. In humans, this enzyme is composed of the telomerase reverse transcriptase (hTERT) and telomerase RNA (hTR) subunits. hTR has been found in t ... Full text Link to item Cite

Bone formation by human postnatal bone marrow stromal stem cells is enhanced by telomerase expression.

Journal Article Nat Biotechnol · June 2002 Human postnatal bone marrow stromal stem cells (BMSSCs) have a limited life-span and progressively lose their stem cell properties during ex vivo expansion. Here we report that ectopic expression of human telomerase reverse transcriptase (hTERT) in BMSSCs ... Full text Link to item Cite

N-terminal domains of the human telomerase catalytic subunit required for enzyme activity in vivo.

Journal Article Mol Cell Biol · November 2001 Most tumor cells depend upon activation of the ribonucleoprotein enzyme telomerase for telomere maintenance and continual proliferation. The catalytic activity of this enzyme can be reconstituted in vitro with the RNA (hTR) and catalytic (hTERT) subunits. ... Full text Link to item Cite

Inhibition of telomerase is related to the life span and tumorigenicity of human prostate cancer cells.

Journal Article J Urol · August 2001 PURPOSE: Telomerase, the enzyme that catalyzes the elongation of telomeres, is illegitimately activated in the majority of cancers, including that of the prostate, where it may greatly extend the life span of malignant cells. The inhibition of telomerase b ... Link to item Cite

A genetically tractable model of human glioma formation.

Journal Article Cancer Res · May 1, 2001 Gliomas remain one of the deadliest forms of cancer. Improved therapeutics will require a better understanding of the molecular nature of these tumors. We, therefore, mimicked the most common genetic changes found in grade III-IV gliomas, disruption of the ... Link to item Cite

The MEK pathway is required for stimulation of p21(WAF1/CIP1) by transforming growth factor-beta.

Journal Article J Biol Chem · December 10, 1999 Transforming growth factor-beta (TGF-beta)can induce the cyclin-dependent kinase inhibitors p21 and p15 in a variety of cell types. We have shown previously that Smad3 is required for the growth inhibitory activity of TGF-beta, whereas overexpression of Sm ... Full text Link to item Cite

Creation of human tumour cells with defined genetic elements.

Journal Article Nature · July 29, 1999 During malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms controlling cellular proliferation. Primary rodent cells are efficiently converted into tumorigenic cells by the coexpression of cooperating oncogen ... Full text Link to item Cite

Characterization of the repeat-tract instability and mutator phenotypes conferred by a Tn3 insertion in RFC1, the large subunit of the yeast clamp loader.

Journal Article Genetics · February 1999 The RFC1 gene encodes the large subunit of the yeast clamp loader (RFC) that is a component of eukaryotic DNA polymerase holoenzymes. We identified a mutant allele of RFC1 (rfc1::Tn3) from a large collection of Saccharomyces cerevisiae mutants that were in ... Full text Link to item Cite

Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization.

Journal Article Proc Natl Acad Sci U S A · December 8, 1998 The immortalization of human cells is a critical step during tumorigenesis. In vitro, normal human somatic cells must overcome two proliferative blockades, senescence and crisis, to become immortal. Transformation with viral oncogenes extends the life span ... Full text Link to item Cite

Expression of TERT in early premalignant lesions and a subset of cells in normal tissues.

Journal Article Nat Genet · June 1998 Activation of telomerase, the enzyme that synthesizes the telomere ends of linear chromosomes, has been implicated in human cell immortalization and cancer cell pathogenesis. Enzyme activity is undetectable in most normal cells and tissues, but present in ... Full text Link to item Cite

Telomerase activity is restored in human cells by ectopic expression of hTERT (hEST2), the catalytic subunit of telomerase.

Journal Article Oncogene · March 5, 1998 The expression of telomerase, the enzyme that synthesizes telomeric DNA de novo, is suppressed in normal somatic human cells but is reactivated during tumorigenesis. This reactivation appears to arrest the normal loss of telomeric DNA incurred as human cel ... Full text Link to item Cite

hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization.

Journal Article Cell · August 22, 1997 Telomerase, the ribonucleoprotein enzyme that elongates telomeres, is repressed in normal human somatic cells but is reactivated during tumor progression. We report the cloning of a human gene, hEST2, that shares significant sequence similarity with the te ... Full text Link to item Cite

The catalytic subunit of yeast telomerase.

Journal Article Proc Natl Acad Sci U S A · August 19, 1997 Telomerase is an RNA-directed DNA polymerase, composed of RNA and protein subunits, that replicates the telomere ends of linear eukaryotic chromosomes. Using a genetic strategy described here, we identify the product of the EST2 gene, Est2p, as a subunit o ... Full text Link to item Cite

The roles of telomeres and telomerase in cell life span.

Journal Article Mutat Res · October 1996 Telomeres cap and protect the ends of chromosomes from degradation and illegitimate recombination. The termini of a linear template cannot, however, be completely replicated by conventional DNA-dependent DNA polymerases, and thus in the absence of a mechan ... Full text Link to item Cite

Telomeres and telomerase in human cancer (review).

Journal Article Int J Oncol · September 1995 Telomerase has recently come into the limelight as one of the most prevalent tumour markers, due to its nearly ubiquitous presence in malignant tissues and absence from most somatic tissues. The essential role of telomeres in unlimited cell proliferation a ... Link to item Cite

Telomerase activity in normal leukocytes and in hematologic malignancies.

Journal Article Blood · May 1, 1995 Telomeres are essential for function and stability of eukaryotic chromosomes. In the absence of telomerase, the enzyme that synthesizes telomeric DNA, telomeres shorten with cell division, a process thought to contribute to cell senescence and the prolifer ... Link to item Cite

Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein-Barr virus-transformed human B lymphocytes.

Journal Article J Virol · May 1994 We have measured telomere length and telomerase activity throughout the life span of clones of human B lymphocytes transformed by Epstein-Barr virus. Shortening of telomeres occurred at similar rates in all populations and persisted until chromosomes had l ... Full text Link to item Cite

Telomerase activity in human ovarian carcinoma.

Journal Article Proc Natl Acad Sci U S A · April 12, 1994 Telomeres fulfill the dual function of protecting eukaryotic chromosomes from illegitimate recombination and degradation and may aid in chromosome attachment to the nuclear membrane. We have previously shown that telomerase, the enzyme which synthesizes te ... Full text Link to item Cite

Telomerase, cell immortality, and cancer.

Journal Article Cold Spring Harb Symp Quant Biol · 1994 Full text Link to item Cite

Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity.

Journal Article EMBO J · May 1992 Loss of telomeric DNA during cell proliferation may play a role in ageing and cancer. Since telomeres permit complete replication of eukaryotic chromosomes and protect their ends from recombination, we have measured telomere length, telomerase activity and ... Full text Link to item Cite