Scholars@Duke
Tso-Pang Yao

Tso-Pang Yao

Professor of Pharmacology and Cancer Biology
Pharmacology & Cancer Biology
yao00001@mc.duke.edu
Duke Box 3813, Durham, NC 27710
C166, LSRC, Box 3813 DUMC, Durham, NC 27710
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Selected Publications

Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.

Journal Article Adv Sci (Weinh) · January 2024 The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain unc ... Full text Open Access Link to item Cite

Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity.

Journal Article J Med Chem · July 27, 2023 In our previous research, a series of phenylsulfonylfuroxan-based hydroxamates were developed, among which compound 1 exhibited remarkable in vitro and in vivo antitumor potency due to its histone deacetylase (HDAC) inhibitory and nitric oxide (NO)-donatin ... Full text Link to item Cite

Parkin regulates neuronal lipid homeostasis through SREBP2-lipoprotein lipase pathway-implications for Parkinson's disease.

Journal Article Hum Mol Genet · April 20, 2023 Abnormal lipid homeostasis has been observed in the brain of Parkinson's disease (PD) patients and experimental models, although the mechanism underlying this phenomenon is unclear. Notably, previous studies have reported that the PD-linked protein Parkin ... Full text Link to item Cite

Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.

Journal Article EMBO Rep · December 6, 2022 Autophagy has emerged as the prime machinery for implementing organelle quality control. In the context of mitophagy, the ubiquitin E3 ligase Parkin tags impaired mitochondria with ubiquitin to activate autophagic degradation. Although ubiquitination is es ... Full text Link to item Cite

Cathelicidin-related antimicrobial peptide mediates skeletal muscle degeneration caused by injury and Duchenne muscular dystrophy in mice.

Journal Article J Cachexia Sarcopenia Muscle · December 2022 BACKGROUND: Cathelicidin, an antimicrobial peptide, plays a key role in regulating bacterial killing and innate immunity; however, its role in skeletal muscle function is unknown. We investigated the potential role of cathelicidin in skeletal muscle pathol ... Full text Open Access Link to item Cite

HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS.

Journal Article Front Cell Dev Biol · 2021 The aberrant translation of a repeat expansion in chromosome 9 open reading frame 72 (C9orf72), the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), results in the accumulation of toxic dipeptide repeat (DPR) prot ... Full text Link to item Cite

RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence.

Journal Article Cell Death Differ · July 2020 The molecular and genetic basis of tumor recurrence is complex and poorly understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, its expression is frequently suppressed in primary tumors. In a transcriptome profiling between ... Full text Link to item Cite

Targeting Histone Deacetylase 6 Reprograms Interleukin-17-Producing Helper T Cell Pathogenicity and Facilitates Immunotherapies for Hepatocellular Carcinoma.

Journal Article Hepatology · June 2020 BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is often accompanied by resistance to immunotherapies despite the presence of tumor-infiltrating lymphocytes. We report that histone deacetylase 6 (HDAC6) represses interleukin-17 (IL-17)-producing helper ... Full text Link to item Cite

PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy.

Journal Article JCI Insight · March 7, 2019 During endochondral bone formation, chondrocyte hypertrophy represents a crucial turning point from chondrocyte differentiation to bone formation. Both parathyroid hormone-related protein (PTHrP) and histone deacetylase 4 (HDAC4) inhibit chondrocyte hypert ... Full text Link to item Cite

CoA synthase regulates mitotic fidelity via CBP-mediated acetylation.

Conference Nat Commun · March 12, 2018 The temporal activation of kinases and timely ubiquitin-mediated degradation is central to faithful mitosis. Here we present evidence that acetylation controlled by Coenzyme A synthase (COASY) and acetyltransferase CBP constitutes a novel mechanism that en ... Full text Open Access Link to item Cite

Discovery of a fluorescent probe with HDAC6 selective inhibition.

Journal Article Eur J Med Chem · December 1, 2017 There is increasing interest in discovering HDAC6 selective inhibitors as chemical probes to elucidate the biological functions of HDAC6 and ultimately as new therapeutic agents. Small-molecular fluorescent probes are widely used to detect target protein l ... Full text Link to item Cite

Mitophagy and neurodegeneration

Chapter · January 1, 2017 Mitochondria, known as the "powerhouse of the cell," are the principal sites of adenosine triphosphate (ATP) production in aerobic, nonphotosynthetic eukaryotic cells. Most classical textbooks depict these double membrane–bound organelles as solitary and s ... Full text Cite

Dopaminergic abnormalities in Hdac6-deficient mice.

Journal Article Neuropharmacology · November 2016 Histone deacetylase 6 (Hdac6), a multifunctional cytoplasmic deacetylase, is abundant in brain. We previously demonstrated that global Hdac6 depletion causes aberrant emotional behaviors in mice. Identification of affected brain systems and its molecular b ... Full text Link to item Cite

HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes.

Journal Article J Cell Sci · April 1, 2016 HDAC6 is a tubulin deacetylase involved in many cellular functions related to cytoskeleton dynamics, including cell migration and autophagy. In addition, HDAC6 affects antigen-dependent CD4(+)T cell activation. In this study, we show that HDAC6 contributes ... Full text Link to item Cite

HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I.

Journal Article EMBO J · February 15, 2016 RIG-I is a key cytosolic sensor that detects RNA viruses through its C-terminal region and activates the production of antiviral interferons (IFNs) and proinflammatory cytokines. While posttranslational modification has been demonstrated to regulate RIG-I ... Full text Link to item Cite

Parkin regulation and neurodegenerative disorders

Journal Article Frontiers in Aging Neuroscience · January 1, 2016 Parkin is a unique, multifunctional ubiquitin ligase whose various roles in the cell, particularly in neurons, are widely thought to be protective. The pivotal role that Parkin plays in maintaining neuronal survival is underscored by our current recognitio ... Full text Cite

HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation.

Journal Article Biochem Biophys Res Commun · September 4, 2015 Mitochondria undergo fusion and fission in response to various metabolic stresses. Growing evidences have suggested that the morphological change of mitochondria by fusion and fission plays a critical role in protecting mitochondria from metabolic stresses ... Full text Link to item Cite

Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling.

Journal Article J Biol Chem · May 29, 2015 Mutations in PARKIN (PARK2), an ubiquitin ligase, cause early onset Parkinson disease. Parkin was shown to bind, ubiquitinate, and target depolarized mitochondria for destruction by autophagy. This process, mitophagy, is considered crucial for maintaining ... Full text Link to item Cite

Chaperone-mediated 26S proteasome remodeling facilitates free K63 ubiquitin chain production and aggresome clearance.

Journal Article J Biol Chem · April 10, 2015 Efficient elimination of misfolded proteins by the proteasome system is critical for proteostasis. Inadequate proteasome capacity can lead to aberrant aggregation of misfolded proteins and inclusion body formation, a hallmark of neurodegenerative disease. ... Full text Link to item Cite

HDAC4 regulates muscle fiber type-specific gene expression programs.

Journal Article Mol Cells · April 2015 Fiber type-specific programs controlled by the transcription factor MEF2 dictate muscle functionality. Here, we show that HDAC4, a potent MEF2 inhibitor, is predominantly localized to the nuclei in fast/glycolytic fibers in contrast to the sarcoplasm in sl ... Full text Link to item Cite

Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.

Journal Article Adv Sci (Weinh) · January 2024 The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain unc ... Full text Open Access Link to item Cite

Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity.

Journal Article J Med Chem · July 27, 2023 In our previous research, a series of phenylsulfonylfuroxan-based hydroxamates were developed, among which compound 1 exhibited remarkable in vitro and in vivo antitumor potency due to its histone deacetylase (HDAC) inhibitory and nitric oxide (NO)-donatin ... Full text Link to item Cite

Parkin regulates neuronal lipid homeostasis through SREBP2-lipoprotein lipase pathway-implications for Parkinson's disease.

Journal Article Hum Mol Genet · April 20, 2023 Abnormal lipid homeostasis has been observed in the brain of Parkinson's disease (PD) patients and experimental models, although the mechanism underlying this phenomenon is unclear. Notably, previous studies have reported that the PD-linked protein Parkin ... Full text Link to item Cite

Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.

Journal Article EMBO Rep · December 6, 2022 Autophagy has emerged as the prime machinery for implementing organelle quality control. In the context of mitophagy, the ubiquitin E3 ligase Parkin tags impaired mitochondria with ubiquitin to activate autophagic degradation. Although ubiquitination is es ... Full text Link to item Cite

Cathelicidin-related antimicrobial peptide mediates skeletal muscle degeneration caused by injury and Duchenne muscular dystrophy in mice.

Journal Article J Cachexia Sarcopenia Muscle · December 2022 BACKGROUND: Cathelicidin, an antimicrobial peptide, plays a key role in regulating bacterial killing and innate immunity; however, its role in skeletal muscle function is unknown. We investigated the potential role of cathelicidin in skeletal muscle pathol ... Full text Open Access Link to item Cite

HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS.

Journal Article Front Cell Dev Biol · 2021 The aberrant translation of a repeat expansion in chromosome 9 open reading frame 72 (C9orf72), the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), results in the accumulation of toxic dipeptide repeat (DPR) prot ... Full text Link to item Cite

RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence.

Journal Article Cell Death Differ · July 2020 The molecular and genetic basis of tumor recurrence is complex and poorly understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, its expression is frequently suppressed in primary tumors. In a transcriptome profiling between ... Full text Link to item Cite

Targeting Histone Deacetylase 6 Reprograms Interleukin-17-Producing Helper T Cell Pathogenicity and Facilitates Immunotherapies for Hepatocellular Carcinoma.

Journal Article Hepatology · June 2020 BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is often accompanied by resistance to immunotherapies despite the presence of tumor-infiltrating lymphocytes. We report that histone deacetylase 6 (HDAC6) represses interleukin-17 (IL-17)-producing helper ... Full text Link to item Cite

PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy.

Journal Article JCI Insight · March 7, 2019 During endochondral bone formation, chondrocyte hypertrophy represents a crucial turning point from chondrocyte differentiation to bone formation. Both parathyroid hormone-related protein (PTHrP) and histone deacetylase 4 (HDAC4) inhibit chondrocyte hypert ... Full text Link to item Cite

CoA synthase regulates mitotic fidelity via CBP-mediated acetylation.

Conference Nat Commun · March 12, 2018 The temporal activation of kinases and timely ubiquitin-mediated degradation is central to faithful mitosis. Here we present evidence that acetylation controlled by Coenzyme A synthase (COASY) and acetyltransferase CBP constitutes a novel mechanism that en ... Full text Open Access Link to item Cite

Discovery of a fluorescent probe with HDAC6 selective inhibition.

Journal Article Eur J Med Chem · December 1, 2017 There is increasing interest in discovering HDAC6 selective inhibitors as chemical probes to elucidate the biological functions of HDAC6 and ultimately as new therapeutic agents. Small-molecular fluorescent probes are widely used to detect target protein l ... Full text Link to item Cite

Mitophagy and neurodegeneration

Chapter · January 1, 2017 Mitochondria, known as the "powerhouse of the cell," are the principal sites of adenosine triphosphate (ATP) production in aerobic, nonphotosynthetic eukaryotic cells. Most classical textbooks depict these double membrane–bound organelles as solitary and s ... Full text Cite

Dopaminergic abnormalities in Hdac6-deficient mice.

Journal Article Neuropharmacology · November 2016 Histone deacetylase 6 (Hdac6), a multifunctional cytoplasmic deacetylase, is abundant in brain. We previously demonstrated that global Hdac6 depletion causes aberrant emotional behaviors in mice. Identification of affected brain systems and its molecular b ... Full text Link to item Cite

HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes.

Journal Article J Cell Sci · April 1, 2016 HDAC6 is a tubulin deacetylase involved in many cellular functions related to cytoskeleton dynamics, including cell migration and autophagy. In addition, HDAC6 affects antigen-dependent CD4(+)T cell activation. In this study, we show that HDAC6 contributes ... Full text Link to item Cite

HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I.

Journal Article EMBO J · February 15, 2016 RIG-I is a key cytosolic sensor that detects RNA viruses through its C-terminal region and activates the production of antiviral interferons (IFNs) and proinflammatory cytokines. While posttranslational modification has been demonstrated to regulate RIG-I ... Full text Link to item Cite

Parkin regulation and neurodegenerative disorders

Journal Article Frontiers in Aging Neuroscience · January 1, 2016 Parkin is a unique, multifunctional ubiquitin ligase whose various roles in the cell, particularly in neurons, are widely thought to be protective. The pivotal role that Parkin plays in maintaining neuronal survival is underscored by our current recognitio ... Full text Cite

HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation.

Journal Article Biochem Biophys Res Commun · September 4, 2015 Mitochondria undergo fusion and fission in response to various metabolic stresses. Growing evidences have suggested that the morphological change of mitochondria by fusion and fission plays a critical role in protecting mitochondria from metabolic stresses ... Full text Link to item Cite

Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling.

Journal Article J Biol Chem · May 29, 2015 Mutations in PARKIN (PARK2), an ubiquitin ligase, cause early onset Parkinson disease. Parkin was shown to bind, ubiquitinate, and target depolarized mitochondria for destruction by autophagy. This process, mitophagy, is considered crucial for maintaining ... Full text Link to item Cite

Chaperone-mediated 26S proteasome remodeling facilitates free K63 ubiquitin chain production and aggresome clearance.

Journal Article J Biol Chem · April 10, 2015 Efficient elimination of misfolded proteins by the proteasome system is critical for proteostasis. Inadequate proteasome capacity can lead to aberrant aggregation of misfolded proteins and inclusion body formation, a hallmark of neurodegenerative disease. ... Full text Link to item Cite

HDAC4 regulates muscle fiber type-specific gene expression programs.

Journal Article Mol Cells · April 2015 Fiber type-specific programs controlled by the transcription factor MEF2 dictate muscle functionality. Here, we show that HDAC4, a potent MEF2 inhibitor, is predominantly localized to the nuclei in fast/glycolytic fibers in contrast to the sarcoplasm in sl ... Full text Link to item Cite

Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity.

Journal Article Protein Cell · January 2015 Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 cannot be fully elucidated with its known substrate ... Full text Link to item Cite

Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity

Journal Article Protein and Cell · January 1, 2015 ABSTRACT: Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 cannot be fully elucidated with its known ... Full text Cite

Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model.

Journal Article Neurodegener Dis · 2015 Aberrant accumulation of protein aggregates is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although a buildup of protein aggregates frequently leads to cell death, whether it is the key pathoge ... Full text Link to item Cite

MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria.

Journal Article J Cell Sci · November 15, 2014 Fasting and glucose shortage activate a metabolic switch that shifts more energy production to mitochondria. This metabolic adaptation ensures energy supply, but also elevates the risk of mitochondrial oxidative damage. Here, we present evidence that metab ... Full text Link to item Cite

Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production.

Journal Article Mol Biol Cell · November 1, 2014 Activation of the inflammatory response is accompanied by a metabolic shift to aerobic glycolysis. Here we identify histone deacetylase 4 (HDAC4) as a new component of the immunometabolic program. We show that HDAC4 is required for efficient inflammatory c ... Full text Link to item Cite

HDAC4 promotes Pax7-dependent satellite cell activation and muscle regeneration.

Journal Article EMBO Rep · November 2014 During muscle regeneration, the transcription factor Pax7 stimulates the differentiation of satellite cells (SCs) toward the muscle lineage but restricts adipogenesis. Here, we identify HDAC4 as a regulator of Pax7-dependent muscle regeneration. In HDAC4-d ... Full text Link to item Cite

PARK2 Induces Autophagy Removal of Impaired Mitochondria via Ubiquitination

Chapter · July 25, 2014 Mutations of PARK2, a gene encoding the ubiquitin ligase Parkin, are causative of autosomal recessive parkinsonism, a neurodegenerative disorder that is characterized by the relentless loss of dopaminergic neurons in the midbrain. The pivotal role that Par ... Full text Cite

Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production.

Journal Article Nat Commun · March 17, 2014 Reversible acetylation of α-tubulin is an evolutionarily conserved modification in microtubule networks. Despite its prevalence, the physiological function and regulation of microtubule acetylation remain poorly understood. Here we report that macrophages ... Full text Link to item Cite

A Mec17-Myosin II Effector Axis Coordinates Microtubule Acetylation and Actin Dynamics to Control Primary Cilium Biogenesis.

Journal Article PLoS One · 2014 Primary cilia are specialized, acetylated microtubule-based signaling processes. Cilium assembly is activated by cellular quiescence and requires reconfiguration of microtubules, the actin cytoskeleton, and vesicular trafficking machinery. How these compon ... Full text Link to item Cite

Proteasomes activate aggresome disassembly and clearance by producing unanchored ubiquitin chains.

Journal Article Mol Cell · September 26, 2013 Aberrant protein aggregation is a dominant pathological feature in neurodegenerative diseases. Protein aggregates cannot be processed by the proteasome; instead, they are frequently concentrated to the aggresome, a perinuclear inclusion body, and subsequen ... Full text Link to item Cite

VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations.

Journal Article Neuron · April 10, 2013 Mutations in VCP cause multisystem degeneration impacting the nervous system, muscle, and/or bone. Patients may present with ALS, Parkinsonism, frontotemporal dementia, myopathy, Paget's disease, or a combination of these. The disease mechanism is unknown. ... Full text Link to item Cite

A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program.

Journal Article Mol Cell · July 13, 2012 Prolonged deficits in neural input activate pathological muscle remodeling, leading to atrophy. In denervated muscle, activation of the atrophy program requires HDAC4, a potent repressor of the master muscle transcription factor MEF2. However, the signalin ... Full text Link to item Cite

Mitochondrial dynamics and Parkinson's disease: focus on parkin.

Journal Article Antioxid Redox Signal · May 1, 2012 SIGNIFICANCE: Parkinson's disease (PD) is a prevalent neurodegenerative disease affecting millions of individuals worldwide. Despite intensive efforts devoted to drug discovery, the disease remains incurable. To provide more effective medical therapy for P ... Full text Link to item Cite

Guidelines for the use and interpretation of assays for monitoring autophagy.

Journal Article Autophagy · April 2012 In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have ... Full text Link to item Cite

Loss of deacetylation activity of Hdac6 affects emotional behavior in mice.

Journal Article PLoS One · 2012 Acetylation is mediated by acetyltransferases and deacetylases, and occurs not only on histones but also on diverse proteins. Although histone acetylation in chromatin structure and transcription has been well studied, the biological roles of non-histone a ... Full text Link to item Cite

Lysine modifications and autophagy.

Journal Article Essays Biochem · 2012 Nutrient deprivation or cellular stress leads to the activation of a catabolic pathway that is conserved across species, known as autophagy. This process is considered to be adaptive and plays an important role in a number of cellular processes, including ... Full text Link to item Cite

Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin.

Journal Article EMBO J · August 16, 2011 Histone deacetylases (HDACs) deacetylate histones and non-histone proteins, thereby affecting protein activity and gene expression. The regulation and function of the cytoplasmic class IIb HDAC6 in endothelial cells (ECs) is largely unexplored. Here, we de ... Full text Link to item Cite

HDACs in skeletal muscle remodeling and neuromuscular disease.

Journal Article Handb Exp Pharmacol · 2011 Skeletal muscle is made of heterogeneous myofibers with different contractile and metabolic properties. The diverse functionality of myofibers enables skeletal muscle to carry out different tasks from maintaining body posture to performing active movements ... Full text Link to item Cite

The discovery of histone deacetylase.

Journal Article Handb Exp Pharmacol · 2011 Link to item Cite

The role of ubiquitin in autophagy-dependent protein aggregate processing

Journal Article Genes and Cancer · December 1, 2010 The efficient management of misfolded protein aggregates is essential for cell viability and requires 3 interconnected pathways: the molecular chaperone machinery that assists protein folding, the proteasome pathway that degrades misfolded proteins, and th ... Full text Cite

Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy.

Journal Article J Cell Biol · May 17, 2010 Mutations in parkin, a ubiquitin ligase, cause early-onset familial Parkinson's disease (AR-JP). How parkin suppresses parkinsonism remains unknown. Parkin was recently shown to promote the clearance of impaired mitochondria by autophagy, termed mitophagy. ... Full text Link to item Cite

Quality control autophagy: a joint effort of ubiquitin, protein deacetylase and actin cytoskeleton.

Journal Article Autophagy · May 2010 Autophagy has been predominantly studied as a nonselective self-digestion process that recycles macromolecules and produces energy in response to starvation. However, autophagy independent of nutrient status has long been known to exist. Recent evidence su ... Full text Open Access Link to item Cite

The microtubule-associated histone deacetylase 6 (HDAC6) regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation.

Journal Article J Biol Chem · April 9, 2010 Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase with tubulin deacetylase activity, and it binds dynein motors. Recent studies revealed that microtubule acetylation affects the affinity and processivity of microtubule motors. These uni ... Full text Link to item Cite

HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy.

Journal Article EMBO J · March 3, 2010 Autophagy is primarily considered a non-selective degradation process induced by starvation. Nutrient-independent basal autophagy, in contrast, imposes intracellular QC by selective disposal of aberrant protein aggregates and damaged organelles, a process ... Full text Link to item Cite

VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD.

Journal Article Autophagy · February 2010 VCP (VCP/p97) is a ubiquitously expressed member of the AAA(+)-ATPase family of chaperone-like proteins that regulates numerous cellular processes including chromatin decondensation, homotypic membrane fusion and ubiquitin-dependent protein degradation by ... Full text Open Access Link to item Cite

Acetylation goes global: the emergence of acetylation biology.

Journal Article Sci Signal · November 17, 2009 For the first 30 years since its discovery, reversible protein acetylation has been studied and understood almost exclusively in the context of histone modification and gene transcription. With the discovery of non-histone acetylated proteins and acetylati ... Full text Link to item Cite

Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway.

Journal Article Mol Cell Biol · November 2009 The maturation of immature chondrocytes to hypertrophic chondrocytes is regulated by parathyroid hormone-related peptide (PTHrP). We demonstrate that PTHrP or forskolin administration can block induction of collagen X-luciferase by exogenous Runx2, MEF2, a ... Full text Link to item Cite

The deacetylase HDAC4 controls myocyte enhancing factor-2-dependent structural gene expression in response to neural activity.

Journal Article FASEB J · January 2009 Histone deacetylase 4 (HDAC4) binds and inhibits activation of the critical muscle transcription factor myocyte enhancer factor-2 (MEF2). However, the physiological significance of the HDAC4-MEF2 complex in skeletal muscle has not been established. Here we ... 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

Effects of downregulated HDAC6 expression on the proliferation of lung cancer cells.

Journal Article Biochem Biophys Res Commun · September 12, 2008 Histone deacetylase 6 (HDAC6) is a multifunctional, cytosolic protein deacetylase that primarily acts on alpha-tubulin. Here we report that stable knockdown of HDAC6 expression causes a decrease in the steady-state level of receptor tyrosine kinases, such ... Full text Link to item Cite

Requirement of HDAC6 for transforming growth factor-beta1-induced epithelial-mesenchymal transition.

Journal Article J Biol Chem · July 25, 2008 The aberrant expression of transforming growth factor (TGF)-beta1 in the tumor microenvironment and fibrotic lesions plays a critical role in tumor progression and tissue fibrosis by inducing epithelial-mesenchymal transition (EMT). EMT promotes tumor cell ... Full text Link to item Cite

Hos2p/Set3p deacetylase complex signals secretory stress through the Mpk1p cell integrity pathway.

Journal Article Eukaryot Cell · July 2008 Perturbations in secretory function activate stress response pathways critical for yeast survival. Here we report the identification of the Hos2p/Set3p deacetylase complex (SET3C) as an essential component of the secretory stress response. Strains lacking ... Full text Link to item Cite

HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization.

Journal Article J Biol Chem · May 9, 2008 Nuclear translocation of beta-catenin is a hallmark of Wnt signaling and is associated with various cancers. In addition to the canonical Wnt pathway activated by Wnt ligands, growth factors such as epidermal growth factor (EGF) also induce beta-catenin di ... Full text Link to item Cite

Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis.

Journal Article Mol Cell Biol · December 2007 Histone deacetylase 6 (HDAC6) is a cytoplasmic deacetylase that uniquely catalyzes alpha-tubulin deacetylation and promotes cell motility. However, the mechanism underlying HDAC6-dependent cell migration and the role for microtubule acetylation in motility ... Full text Link to item Cite

The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming.

Journal Article J Biol Chem · November 16, 2007 Neural activity actively regulates muscle gene expression. This regulation is crucial for specifying muscle functionality and synaptic protein expression. How neural activity is relayed into nuclei and connected to the muscle transcriptional machinery, how ... Full text Link to item Cite

The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2.

Journal Article J Biol Chem · October 5, 2007 Ataxin-1 is a neurodegenerative disorder protein whose mutant form causes spinocerebellar ataxia type-1 (SCA1). Evidence suggests that ataxin-1 may function as a transcription repressor. However, neither the importance of this putative transcriptional repr ... Full text Link to item Cite

HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates.

Journal Article Genes Dev · September 1, 2007 A cellular defense mechanism counteracts the deleterious effects of misfolded protein accumulation by eliciting a stress response. The cytoplasmic deacetylase HDAC6 (histone deacetylase 6) was previously shown to be a key element in this response by coordi ... Full text Link to item Cite

HDAC6 modulates cell motility by altering the acetylation level of cortactin.

Journal Article Mol Cell · July 20, 2007 Histone deacetylase 6 (HDAC6) is a tubulin-specific deacetylase that regulates microtubule-dependent cell movement. In this study, we identify the F-actin-binding protein cortactin as a HDAC6 substrate. We demonstrate that HDAC6 binds cortactin and that ov ... Full text Link to item Cite

Solution structure of the Ubp-M BUZ domain, a highly specific protein module that recognizes the C-terminal tail of free ubiquitin.

Journal Article J Mol Biol · July 6, 2007 The BUZ/Znf-UBP domain is a distinct ubiquitin-binding module found in the cytoplasmic deacetylase HDAC6, the E3 ubiquitin ligase BRAP2/IMP, and a subfamily of deubiquitinating enzymes. Here, we report the solution structure of the BUZ domain of Ubp-M, a u ... Full text Link to item Cite

HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS.

Journal Article Nature · June 14, 2007 A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechan ... Full text Link to item Cite

HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions.

Journal Article J Cell Sci · April 15, 2007 Genetic or pharmacological alteration of the activity of the histone deacetylase 6 (HDAC6) induces a parallel alteration in cell migration. Using tubacin to block deacetylation of alpha-tubulin, and not other HDAC6 substrates, yielded a motility reduction ... Full text Link to item Cite

Merlin facilitates ubiquitination and degradation of transactivation-responsive RNA-binding protein.

Journal Article Oncogene · February 23, 2006 The Nf2 tumor suppressor codes for merlin, a protein whose function is largely unknown. We have previously demonstrated a novel interaction between merlin and TRBP, which inhibits the oncogenic activity of TRBP. In spite of the significance of their functi ... Full text Link to item Cite

Charge modification at multiple C-terminal lysine residues regulates p53 oligomerization and its nucleus-cytoplasm trafficking.

Journal Article J Biol Chem · January 20, 2006 The basal level of the tumor suppressor p53 is regulated by MDM2-mediated ubiquitination at specific lysines, which leads to p53 nuclear export and degradation. Upon p53 activation, however, these lysines become acetylated by p300/CREB-binding protein. Her ... Full text Link to item Cite

Histone deacetylase 3 binds to and regulates the GCMa transcription factor.

Journal Article Nucleic Acids Res · 2006 Human GCMa transcription factor regulates expression of syncytin, a placental fusogenic protein mediating trophoblastic fusion. Recently, we have demonstrated that CBP-mediated GCMa acetylation underlies the activated cAMP/PKA signaling pathway that stimul ... Full text Link to item Cite

Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death.

Journal Article J Neurosci · October 12, 2005 Histone deacetylase 4 (HDAC4) undergoes signal-dependent shuttling between the cytoplasm and nucleus, which is regulated in part by calcium/calmodulin-dependent kinase (CaMK)-mediated phosphorylation. Here, we report that HDAC4 intracellular trafficking is ... Full text Link to item Cite

Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone.

Journal Article J Biol Chem · October 7, 2005 It is known that inhibition of histone deacetylases (HDACs) leads to acetylation of the abundant protein chaperone hsp90. In a recent study, we have shown that knockdown of HDAC6 by a specific small interfering RNA leads to hyperacetylation of hsp90 and th ... Full text Link to item Cite

A mechanism of COOH-terminal binding protein-mediated repression.

Journal Article Mol Cancer Res · October 2005 The E2F4 and E2F5 proteins specifically associate with the Rb-related p130 protein in quiescent cells to repress transcription of various genes encoding proteins important for cell growth. A series of reports has provided evidence that Rb-mediated repressi ... Full text Link to item Cite

Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications.

Journal Article Mol Cell Biol · October 2005 The class II deacetylase histone deacetylase 4 (HDAC4) negatively regulates the transcription factor MEF2. HDAC4 is believed to repress MEF2 transcriptional activity by binding to MEF2 and catalyzing local histone deacetylation. Here we report that HDAC4 a ... Full text Link to item Cite

Stimulation of GCMa transcriptional activity by cyclic AMP/protein kinase A signaling is attributed to CBP-mediated acetylation of GCMa.

Journal Article Mol Cell Biol · October 2005 Human GCMa is a zinc-containing transcription factor primarily expressed in placenta. GCMa regulates expression of syncytin gene, which encodes for a placenta-specific membrane protein that mediates trophoblastic fusion and the formation of syncytiotrophob ... Full text Link to item Cite

HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor.

Journal Article Mol Cell · May 27, 2005 The molecular chaperone heat shock protein 90 (Hsp90) and its accessory cochaperones function by facilitating the structural maturation and complex assembly of client proteins, including steroid hormone receptors and selected kinases. By promoting the acti ... Full text Link to item Cite

The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase.

Journal Article Cancer Res · May 1, 2005 Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target oncogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis und ... Full text Link to item Cite

Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment.

Journal Article J Biol Chem · April 29, 2005 The cyclin D1 gene encodes the labile serum-inducible regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein. Overexpression of cyclin D1 promotes cellular proliferation and normal physiological levels of cyclin D ... Full text Link to item Cite

FBW2 targets GCMa to the ubiquitin-proteasome degradation system.

Journal Article J Biol Chem · March 18, 2005 The GCM proteins GCMa/1 and GCMb/2 are novel zinc-containing transcription factors critical for glial cell differentiation in fly and for placental as well as parathyroid gland development in mouse. Previous pulse-chase experiments have demonstrated differ ... Full text Link to item Cite

AcK-knowledge reversible acetylation.

Journal Article Sci STKE · August 3, 2004 In 1966, the histone was identified as the first protein subject to reversible acetylation. The ensuing 30 years of research on histone acetylation has been critical for elucidating how gene transcription and chromatin remodeling are regulated at the molec ... Full text Link to item Cite

Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases.

Journal Article J Biol Chem · February 27, 2004 Affinity isolation of protein serine/threonine phosphatases on the immobilized phosphatase inhibitor microcystin-LR identified histone deacetylase 1(HDAC1), HDAC6, and HDAC10 as novel components of cellular phosphatase complexes. Other HDACs, specifically ... Full text Link to item Cite

The HDAC complex and cytoskeleton.

Journal Article Novartis Found Symp · 2004 HDAC6 is a cytoplasmic deacetylase that dynamically associates with the microtubule and actin cytoskeletons. HDAC6 regulates growth factor-induced chemotaxis by its unique deacetylase activity towards microtubules or other substrates. Here we describe a no ... Link to item Cite

The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress.

Journal Article Cell · December 12, 2003 The efficient clearance of cytotoxic misfolded protein aggregates is critical for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggres ... Full text Link to item Cite

Regulation of E2A activities by histone acetyltransferases in B lymphocyte development.

Journal Article J Biol Chem · January 24, 2003 Genetic studies have demonstrated that the basic helix-loop-helix protein E2A is an essential transcription factor in B lymphocyte lineage commitment and differentiation. However, the mechanism underlying E2A-mediated transcription regulation is not fully ... Full text Link to item Cite

MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation.

Journal Article EMBO J · November 15, 2002 The tumor suppressor p53 is stabilized and activated in response to cellular stress through post-translational modifications including acetylation. p300/CBP-mediated acetylation of p53 is negatively regulated by MDM2. Here we show that MDM2 can promote p53 ... Full text Link to item Cite

HDAC6 is a microtubule-associated deacetylase.

Journal Article Nature · May 23, 2002 Reversible acetylation of alpha-tubulin has been implicated in regulating microtubule stability and function. The distribution of acetylated alpha-tubulin is tightly controlled and stereotypic. Acetylated alpha-tubulin is most abundant in stable microtubul ... Full text Link to item Cite

Molecular cloning and characterization of a novel histone deacetylase HDAC10.

Journal Article J Biol Chem · February 1, 2002 The growing number of proteins controlled by reversible acetylation suggests the existence of a large number of acetyltransferases and deacetylases. Here, we report the identification of a novel class II histone deacetylase, HDAC10. Homology comparison ind ... Full text Link to item Cite

The modular nature of histone deacetylase HDAC4 confers phosphorylation-dependent intracellular trafficking.

Journal Article J Biol Chem · September 14, 2001 In C2C12 myoblasts, endogenous histone deacetylase HDAC4 shuttles between cytoplasmic and nuclear compartments, supporting the hypothesis that its subcellular localization is dynamically regulated. However, upon differentiation, this dynamic equilibrium is ... Full text Link to item Cite

Role of T-bet in commitment of TH1 cells before IL-12-dependent selection.

Journal Article Science · June 8, 2001 How cytokines control differentiation of helper T (TH) cells is controversial. We show that T-bet, without apparent assistance from interleukin 12 (IL-12)/STAT4, specifies TH1 effector fate by targeting chromatin remodeling to individual interferon-gamma ( ... Full text Link to item Cite

p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2.

Journal Article EMBO J · March 15, 2001 The tumor suppressor p53 is activated in response to many types of cellular and environmental insults via mechanisms involving post-translational modification. Here we demonstrate that, unlike phosphorylation, p53 invariably undergoes acetylation in cells ... Full text Link to item Cite

A stimulus-specific role for CREB-binding protein (CBP) in T cell receptor-activated tumor necrosis factor alpha gene expression.

Journal Article Proc Natl Acad Sci U S A · April 11, 2000 The cAMP response element binding protein (CREB)-binding protein (CBP)/p300 family of coactivator proteins regulates gene transcription through the integration of multiple signal transduction pathways. Here, we show that induction of tumor necrosis factor ... Full text Link to item Cite

Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP.

Journal Article Genes Dev · February 1, 2000 Mice with monoallelic inactivation of the CBP gene develop highly penetrant, multilineage defects in hematopoietic differentiation and, with advancing age, an increased incidence of hematologic malignancies. The latter are characterized, at least in some c ... Link to item Cite

SMRTER, a Drosophila nuclear receptor coregulator, reveals that EcR-mediated repression is critical for development.

Journal Article Mol Cell · August 1999 The Drosophila ecdysone receptor (EcR)/ultraspiracle (USP) heterodimer is a key regulator in molting and metamorphoric processes, activating and repressing transcription in a sequence-specific manner. Here, we report the isolation of an EcR-interacting pro ... Full text Link to item Cite

Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia.

Journal Article J Biol Chem · July 17, 1998 During melanocyte development, the cytokine Steel factor activates its receptor c-Kit, initiating a signal transduction cascade, which is vital for lineage determination via unknown downstream nuclear targets. c-Kit has recently been found to trigger mitog ... Full text Link to item Cite

Distinct roles of the co-activators p300 and CBP in retinoic-acid-induced F9-cell differentiation.

Journal Article Nature · May 21, 1998 The related proteins p300 and CBP (cAMP-response-element-binding protein (CREB)-binding protein)) are transcriptional co-activators that act with other factors to regulate gene expression and play roles in many cell-differentiation and signal transduction ... Full text Link to item Cite

Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300.

Journal Article Cell · May 1, 1998 The transcriptional coactivator and integrator p300 and its closely related family member CBP mediate multiple, signal-dependent transcriptional events. We have generated mice lacking a functional p300 gene. Animals nullizygous for p300 died between days 9 ... Full text Link to item Cite

The nuclear hormone receptor coactivator SRC-1 is a specific target of p300.

Journal Article Proc Natl Acad Sci U S A · October 1, 1996 p300 and its family member, CREB-binding protein (CBP), function as key transcriptional coactivators by virtue of their interaction with the activated forms of certain transcription factors. In a search for additional cellular targets of p300/CBP, a protei ... Full text Link to item Cite

Interaction and functional collaboration of p300/CBP and bHLH proteins in muscle and B-cell differentiation.

Journal Article Genes Dev · October 1, 1996 Differentiation of skeletal muscle cells and B lymphocytes is regulated by basic helix-loop-helix (bHLH) proteins. Both differentiation programs are inhibited by the adenovirus E1A oncoprotein. Analysis of E1A mutants has implicated two of its cellular-bin ... Full text Link to item Cite

Ecdysone-inducible gene expression in mammalian cells and transgenic mice.

Journal Article Proc Natl Acad Sci U S A · April 16, 1996 During metamorphosis of Drosophila melanogaster, a cascade of morphological changes is triggered by the steroid hormone 20-OH ecdysone via the ecdysone receptor, a member of the nuclear receptor superfamily. In this report, we have transferred insect hormo ... Full text Link to item Cite

Seven-up inhibits ultraspiracle-based signaling pathways in vitro and in vivo.

Journal Article Mol Cell Biol · December 1995 Seven-up (Svp), the Drosophila homolog of the chicken ovalbumin upstream transcription factor (COUP-TF); Ultraspiracle (Usp), the Drosophila homolog of the retinoid X receptor; and the ecdysone receptor are all members of the nuclear/steroid receptor super ... Full text Link to item Cite

Identification and characterization of a Drosophila nuclear receptor with the ability to inhibit the ecdysone response.

Journal Article Proc Natl Acad Sci U S A · November 7, 1995 In a search for retinoid X receptor-like molecules in Drosophila, we have identified an additional member of the nuclear receptor superfamily, XR78E/F. In the DNA-binding domain, XR78E/F is closely related to the mammalian receptor TR2, as well as to the n ... Full text Link to item Cite

Functional ecdysone receptor is the product of EcR and Ultraspiracle genes.

Journal Article Nature · December 2, 1993 Although the biological activity of the insect moulting hormone ecdysone, is manifested through a hormonally regulated transcriptional cascade associated with chromosomal puffing, a direct association of the receptor with the puff has yet to be established ... Full text Link to item Cite

Drosophila ultraspiracle modulates ecdysone receptor function via heterodimer formation.

Journal Article Cell · October 2, 1992 The vertebrate retinoid X receptor (RXR) has been implicated in the regulation of multiple hormonal signaling pathways through the formation of heteromeric receptor complexes that bind DNA with high affinity. We now demonstrate that ultraspiracle (usp), a ... Full text Link to item Cite

Alternative translation initiation site usage results in two structurally distinct forms of Pit-1.

Journal Article J Biol Chem · July 15, 1991 Pit-1 is a pituitary-specific transcription factor that plays a critical role in the normal development of the anterior pituitary gland. Previous analyses have shown that this protein exists in the rat pituitary gland and in rat pituitary-derived cell line ... Link to item Cite