Both the Activity and Stability of the Transcriptional Repressor PLZF Are Modified by the Class III Histone Deacetylase SIRT1.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 360-360
Author(s):  
Melanie-Jane McConnell ◽  
Emma Langley ◽  
Yolanda Martinez-Martinez ◽  
Tony Kouzarides ◽  
Jonathan D. Licht
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Transcriptional Repressor ◽  
Model Organisms ◽  
Class Iii ◽  
Endogenous Proteins ◽  
Co Precipitation ◽  
Protein Deacetylase

Abstract The transcription factor PLZF is expressed in hematopoietic development and rearranged in t(11;17) acute promyelocytic leukemia (APL). PLZF expression is high in the quiescent progenitor CD34+ cell, and declines during differentiation along myeloid and erythroid lineages. PLZF encodes a BTB-Zinc finger transcriptional repressor that inhibits the cell cycle through inhibition of targets genes such as cyclin A and c-myc through the recruitment of histone deacetylase complexes. However, PLZF itself is regulated by acetylation. In a separate study we demonstrate that acetylation of PLZF by p300/CBP enhances the transcriptional repression activity of PLZF. Through a yeast two-hybrid study we found that PLZF associates with the protein deacetylase SIRT1. SIRT1 is a member of the sirtuin family of class III histone deacetylases. In model organisms such as yeast, worms and flies, sirtuins play a common role in lifespan extension. The interaction between PLZF and SIRT1 was confirmed by co-precipitation of endogenous proteins and localized to the zinc fingers of PLZF, the region targeted for acetylation by p300/CBP. Acetylation of PLZF mediated by p300/CBP was reversed by SIRT1. Furthermore while acetylation of PLZF enhances its ability to repress transcription, co-expression of SIRT1 decreased PLZF transcriptional repression activity, consistent with loss of acetylation. Conversely, inhibition of SIRT1 activity with nicotinamide enhanced both PLZF acetylation and transcriptional repression of PLZF on its endogenous target gene c-myc. Further, increasing PLZF acetylation by inhibition of SIRT1 was associated with decreased PLZF stability. Acetyl-PLZF levels were stabilized by inhibition of the proteosomal degradation machinery, together implying that PLZF acetylation and activation results in increased protein turnover. These data point to the increasing complexity of the role of acetylation in transcriptional regulation and stand in contrast with data for the related Bcl6 repressor where acetylation of the protein inhibits repression. These data also indicate a novel function for sirtuins in regulation of transcriptional repression.

scholarly journals The Rpd3-Sin3 Histone Deacetylase Regulates Replication Timing and Enables Intra-S Origin Control in Saccharomyces cerevisiae

2004 ◽  
Vol 24 (11) ◽  
pp. 4769-4780 ◽  
Author(s):  
Jennifer G. Aparicio ◽  
Christopher J. Viggiani ◽  
Daniel G. Gibson ◽  
Oscar M. Aparicio
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Replication Timing ◽  
Histone Deacetylation ◽  
Origin Firing ◽  
Replication Checkpoint ◽  
Genome Transcription ◽  
Late Origin

ABSTRACT The replication of eukaryotic genomes follows a temporally staged program, in which late origin firing often occurs within domains of altered chromatin structure(s) and silenced genes. Histone deacetylation functions in gene silencing in some late-replicating regions, prompting an investigation of the role of histone deacetylation in replication timing control in Saccharomyces cerevisiae. Deletion of the histone deacetylase Rpd3 or its interacting partner Sin3 caused early activation of late origins at internal chromosomal loci but did not alter the initiation timing of early origins or a late-firing, telomere-proximal origin. By delaying initiation relative to the earliest origins, Rpd3 enables regulation of late origins by the intra-S replication checkpoint. RPD3 deletion suppresses the slow S phase of clb5Δ cells by enabling late origins to fire earlier, suggesting that Rpd3 modulates the initiation timing of many origins throughout the genome. Examination of factors such as Ume6 that function together with Rpd3 in transcriptional repression indicates that Rpd3 regulates origin initiation timing independently of its role in transcriptional repression. This supports growing evidence that for much of the S. cerevisiae genome transcription and replication timing are not linked.

scholarly journals Functional Domains of c-myc Promoter Binding Protein 1 Involved in Transcriptional Repression and Cell Growth Regulation

1999 ◽  
Vol 19 (4) ◽  
pp. 2880-2886 ◽  
Author(s):  
Asish K. Ghosh ◽  
Robert Steele ◽  
Ratna B. Ray
Keyword(s):  
Amino Acids ◽  
Cell Growth ◽  
Dna Binding ◽  
Transcriptional Repression ◽  
Growth Regulation ◽  
Transcriptional Repressor ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Repressor Activity

ABSTRACT We initially identified c-myc promoter binding protein 1 (MBP-1), which negatively regulates c-myc promoter activity, from a human cervical carcinoma cell expression library. Subsequent studies on the biological role of MBP-1 demonstrated induction of cell death in fibroblasts and loss of anchorage-independent growth, reduced invasive ability, and tumorigenicity of human breast carcinoma cells. To investigate the potential role of MBP-1 as a transcriptional regulator, a chimeric protein containing MBP-1 fused to the DNA binding domain of the yeast transactivator factor GAL4 was constructed. This fusion protein exhibited repressor activity on the herpes simplex virus thymidine kinase promoter via upstream GAL4 DNA binding sites. Structure-function analysis of mutant MBP-1 in the context of the GAL4 DNA binding domain revealed that MBP-1 transcriptional repressor domains are located in the N terminus (amino acids 1 to 47) and C terminus (amino acids 232 to 338), whereas the activation domain lies in the middle (amino acids 140 to 244). The N-terminal domain exhibited stronger transcriptional repressor activity than the C-terminal region. When the N-terminal repressor domain was transferred to a potent activator, transcription was strongly inhibited. Both of the repressor domains contained hydrophobic regions and had an LXVXL motif in common. Site-directed mutagenesis in the repressor domains indicated that the leucine residues in the LXVXL motif are required for transcriptional repression. Mutation of the leucine residues in the common motif of MBP-1 also abrogated the repressor activity on the c-mycpromoter. In addition, the leucine mutant forms of MBP-1 failed to suppress cell growth in fibroblasts like wild-type MBP-1. Taken together, our results indicate that MBP-1 is a complex cellular factor containing multiple transcriptional regulatory domains that play an important role in cell growth regulation.

scholarly journals The Role of Sirtuins in Kidney Diseases

2020 ◽  
Vol 21 (18) ◽  
pp. 6686
Author(s):  
Yu Ah Hong ◽  
Ji Eun Kim ◽  
Minjee Jo ◽  
Gang-Jee Ko
Keyword(s):  
Histone Deacetylases ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Expression Profiles ◽  
Kidney Injury ◽  
Class Iii ◽  
Cellular Functions ◽  
Wide Range

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

The Critical Role of the Class III Histone Deacetylase SIRT1 in Cancer

2009 ◽  
Vol 69 (5) ◽  
pp. 1702-1705 ◽  
Author(s):  
Tao Liu ◽  
Pei Y. Liu ◽  
Glenn M. Marshall
Keyword(s):  
Histone Deacetylase ◽  
Critical Role ◽  
Class Iii

scholarly journals Homeodomain-Interacting Protein Kinase 1 Modulates Daxx Localization, Phosphorylation, and Transcriptional Activity

2003 ◽  
Vol 23 (3) ◽  
pp. 950-960 ◽  
Author(s):  
Jeffrey A. Ecsedy ◽  
Jennifer S. Michaelson ◽  
Philip Leder
Keyword(s):  
Protein Kinase ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Transcriptional Activity ◽  
Transcriptional Repressor ◽  
Transcriptional Regulators ◽  
Kinase Domain ◽  
Promyelocytic Leukemia ◽  
Interacting Protein ◽  
Promyelocytic Leukemia Protein

ABSTRACT We describe an interaction between homeodomain-interacting protein kinase 1 (HIPK1) and Daxx, two transcriptional regulators important in transducing growth-regulatory signals. We demonstrate that HIPK1 is ubiquitously expressed in mice and humans and localizes predominantly to the nucleus. Daxx normally resides within the nucleus in promyelocytic leukemia protein (PML) oncogenic domains (PODs), where it physically interacts with PML. Under certain circumstances, Daxx is relocalized from PODs to chromatin, where it then acts as a transcriptional repressor through an association with histone deacetylase (HDAC1). We propose two novel mechanisms for regulating the activity of Daxx, both mediated by HIPK1. First, HIPK1 physically interacts with Daxx in cells and consequently relocalizes Daxx from PODs. Daxx relocalization disrupts its interaction with PML and augments its interaction with HDAC1, likely influencing Daxx activity. Although the relocalization of Daxx from PODs is phosphorylation independent, an active HIPK1 kinase domain is required, suggesting that HIPK1 autophosphorylation is important in this interaction. Second, HIPK1 phosphorylates Daxx on Ser 669, and phosphorylation of this site is important in modulating the ability of Daxx to function as a transcriptional repressor. Mutation of Daxx Ser 669 to Ala results in increased repression in three of four transcriptional reporters, suggesting that phosphorylation by HIPK1 diminishes Daxx transcriptional repression of specific promoters. Taken together, our results indicate that HIPK1 and Daxx collaborate in regulating transcription.

scholarly journals Retinoblastoma Protein Disrupts Interactions Required for RNA Polymerase III Transcription

2000 ◽  
Vol 20 (24) ◽  
pp. 9192-9202 ◽  
Author(s):  
Josephine E. Sutcliffe ◽  
Timothy R. P. Brown ◽  
Simon J. Allison ◽  
Pamela H. Scott ◽  
Robert J. White
Keyword(s):  
Rna Polymerase ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Rna Polymerase Iii ◽  
Retinoblastoma Protein ◽  
Class Iii ◽  
Negative Effect ◽  
Pol Iii

ABSTRACT The retinoblastoma protein (RB) has been shown to suppress RNA polymerase (Pol) III transcription in vivo (R. J. White, D. Trouche, K. Martin, S. P. Jackson, and T. Kouzarides, Nature 382:88–90, 1996). This regulation involves interaction with TFIIIB, a multisubunit factor that is required for the expression of all Pol III templates (C. G. C. Larminie, C. A. Cairns, R. Mital, K. Martin, T. Kouzarides, S. P. Jackson, and R. J. White, EMBO J. 16:2061–2071, 1997; W.-M. Chu, Z. Wang, R. G. Roeder, and C. W. Schmid, J. Biol. Chem. 272:14755–14761, 1997). However, it has not been established why RB binding to TFIIIB results in transcriptional repression. For several Pol II-transcribed genes, RB has been shown to inhibit expression by recruiting histone deacetylases, which are thought to decrease promoter accessibility. We present evidence that histone deacetylases exert a negative effect on Pol III activity in vivo. However, RB remains able to regulate Pol III transcription in the presence of the histone deacetylase inhibitor trichostatin A. Instead, RB represses by disrupting interactions between TFIIIB and other components of the basal Pol III transcription apparatus. Recruitment of TFIIIB to most class III genes requires its binding to TFIIIC2, but this can be blocked by RB. In addition, RB disrupts the interaction between TFIIIB and Pol III that is essential for transcription. The ability of RB to inhibit these key interactions can explain its action as a potent repressor of class III gene expression.

Histone Acetyltransferase Activity of p300 Is Required for Transcriptional Repression by the Promyelocytic Leukemia Zinc Finger Protein.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 359-359
Author(s):  
Fabien Guidez ◽  
Louise Howell ◽  
Mark Isalan ◽  
Marek Cebrat ◽  
Rhoda M. Alani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Binding ◽  
Histone Deacetylase ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Hematopoietic Stem

Abstract The Promyelocytic Leukemia Zinc Finger (PLZF) gene was identified in a rare case of acute promyelocytic leukemia (APL) with translocation t(11;17)(q23;q21) and resistance to therapy with all-trans-retinoic acid. Recent studies have indicated a critical role of PLZF in maintenance of spermatogonial stem cells. Prominent expression of PLZF in hematopoietic stem cells, suggest that it may also play a similar role in this compartment. The wild type PLZF protein is a DNA sequence-specific transcription repressor containing nine Krüppel-like C2-H2 zinc fingers and an N-terminal BTB/POZ repression domain. Transcriptional repression by PLZF is mediated through recruitment of the nuclear receptor co-repressor (N-CoR/SMRT)/histone deacetylase (HDAC) complexes to its target genes, such as c-MYC and HOX genes. We now show that transcriptional repression by PLZF is surprisingly also dependent on the histone acetyl transferase (HAT) activity of the p300 protein. PLZF associates with p300 in vivo and its ability to repress transcription is specifically dependent on acetylation of PLZF on lysines in its C-terminal C2-H2 zinc-finger motifs. Acetylation of PLZF enhances its ability to bind its cognate DNA binding site in vitro as determined by EMSA and in vivo as measured by chromatin immunoprecipitation. An acetylation site mutant of PLZF fails to repress transcription despite retaining its abilities to interact with co-repressor/HDAC complexes, due to inefficient DNA binding. Inhibitors of p300 abolish transcriptional repression by PLZF and mutants of PLZF that mimic acetylation were insensitive to these inhibitory effects. Acetylation of PLZF by p300 was specific since over-expression of another HAT, p/CAF or the selective inhibition of p/CAF had no effect on PLZF activity despite the ability of the proteins to associate with each other. Taken together, our results indicate that a histone deacetylase dependent transcriptional repressor can be positively regulated through acetylation and point to an unexpected role of a co-activator protein in transcriptional repression.

scholarly journals INSM1 functions as a transcriptional repressor of the neuroD/β2 gene through the recruitment of cyclin D1 and histone deacetylases

2006 ◽  
Vol 397 (1) ◽  
pp. 169-177 ◽  
Author(s):  
Wei-Dong Liu ◽  
Hong-Wei Wang ◽  
Michelle Muguira ◽  
Mary B. Breslin ◽  
Michael S. Lan
Keyword(s):  
Cyclin D1 ◽  
Chromatin Immunoprecipitation ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Transcriptional Repressor ◽  
Chromatin Immunoprecipitation Assay ◽  
Immunoprecipitation Assay ◽  
Repressor Activity

INSM1/IA-1 (insulinoma-associated 1) is a developmentally regulated zinc-finger transcription factor, exclusively expressed in the foetal pancreas and nervous system, and in tumours of neuroendocrine origin. We have identified an INSM1 binding site in the neuroD/β2 promoter and demonstrated transcriptional repressor activity of INSM1 by transient transfection assay. A chromatin immunoprecipitation assay confirmed that in vivo INSM1 is situated on the promoter region of the neuroD/β2 gene. In an attempt to elucidate the molecular mechanism of transcriptional repression by the INSM1 gene, cyclin D1 was identified as an interacting protein by using a 45-day-old human foetal brain cDNA library and a yeast two-hybrid screen. The physical association between INSM1 and cyclin D1 was confirmed by in vitro and in vivo pull-down assay. Cyclin D1 co-operates with INSM1 and suppresses neuroD/β2 promoter activity. Co-immunoprecipitation of INSM1, cyclin D1 and HDACs (histone deacetylases) in mammalian cells revealed that INSM1 interacts with HDAC-1 and -3 and that this interaction is mediated through cyclin D1. Overexpression of cyclin D1 and HDAC-3 significantly enhanced the transcriptional repression activity of INSM1 on the neuroD/β2 promoter. A further chromatin immunoprecipitation assay confirmed that HDAC-3 occupies this same region of the neuroD/β2 promoter, by forming a transcription complex with INSM1. Thus we conclude that INSM1 recruits cyclin D1 and HDACs, which confer transcriptional repressor activity.

scholarly journals Regulating the Regulators: The Role of Histone Deacetylase 1 (HDAC1) in Erythropoiesis

2020 ◽  
Vol 21 (22) ◽  
pp. 8460
Author(s):  
Min Young Kim ◽  
Bowen Yan ◽  
Suming Huang ◽  
Yi Qiu
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Gene Activation ◽  
Bhlh Transcription Factor ◽  
Nucleosome Remodeling ◽  
Hdac Activity ◽  
Histone Deacetylase 1

Histone deacetylases (HDACs) play important roles in transcriptional regulation in eukaryotic cells. Class I deacetylase HDAC1/2 often associates with repressor complexes, such as Sin3 (Switch Independent 3), NuRD (Nucleosome remodeling and deacetylase) and CoREST (Corepressor of RE1 silencing transcription factor) complexes. It has been shown that HDAC1 interacts with and modulates all essential transcription factors for erythropoiesis. During erythropoiesis, histone deacetylase activity is dramatically reduced. Consistently, inhibition of HDAC activity promotes erythroid differentiation. The reduction of HDAC activity not only results in the activation of transcription activators such as GATA-1 (GATA-binding factor 1), TAL1 (TAL BHLH Transcription Factor 1) and KLF1 (Krüpple-like factor 1), but also represses transcription repressors such as PU.1 (Putative oncogene Spi-1). The reduction of histone deacetylase activity is mainly through HDAC1 acetylation that attenuates HDAC1 activity and trans-repress HDAC2 activity through dimerization with HDAC1. Therefore, the acetylation of HDAC1 can convert the corepressor complex to an activator complex for gene activation. HDAC1 also can deacetylate non-histone proteins that play a role on erythropoiesis, therefore adds another layer of gene regulation through HDAC1. Clinically, it has been shown HDACi can reactivate fetal globin in adult erythroid cells. This review will cover the up to date research on the role of HDAC1 in modulating key transcription factors for erythropoiesis and its clinical relevance.

scholarly journals Histone Deacetylase Inhibitors As Potential Therapeutic Agents For Various Disorders

2019 ◽  
Vol 5 (2) ◽  
pp. 235-253
Author(s):  
Kajal Thapa ◽  
Savir Kumar ◽  
Anurag Sharma ◽  
Sandeep Arora ◽  
Amarjot Kaur Grewal ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Epigenetic Modification ◽  
Histone Acetyltransferases ◽  
Lysine Acetylation ◽  
Histone Deacetylases Inhibitors ◽  
Nucleosomal Array ◽  
Key Factor

Epigenetic modification acetylation or deacetylation of histone considered as an important element in various disorders. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are the enzymes which catalyse the acetylation and deacetylation of histone respectively. It helps in regulating the condensation of chromatin and transcription of genes. Lysine acetylation and deacetylation present on the nucleosomal array of histone is the key factor for gene expression and regulation in a normal working living cell. Modification in histone protein will lead to the development of cancer and can cause various neurodegenerative disorders. To safeguard the cells or histone proteins from these diseases histone deacetylase inhibitors are used. In this review, the main focus is upon the role of histone deacetylases inhibitors in various diseases.

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