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Chromosomal localization of the mouse HDAC2 gene. A, metaphase chromosomes hybridized with a mouse HDAC2 genomic probe from the clone DASHII8. Arrows indicate specific hybridization signals. B, metaphase chromosomes hybridized with both the mouse HDAC2 genomic probe and a probe specific for the centromeric region of chromosome 10. The small arrow indicates the hybridization signal for the mouse HDAC2 gene, and the large arrow indicates the signal for centromeric region of chromosome 10. C, schematic drawing of the mouse chromosome 10. The arrow indicates the labeled site with the mouse HDAC2 gene.
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Histone deacetylase-2 (HDAC2) is a component of a complex that mediates transcriptional repression in mammalian cells. A mouse HDAC2 cDNA was used to identify several recombinant clones containing the entire mouse HDAC2 gene. The mouse HDAC2 gene spans over 36 kilobase pairs and is composed of 14 exons (ranging from 58 to 362 nucleotides in length)...
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We have cloned and sequenced genomic DNA from a human library extending 1300 bp upstream the 5'-untranslated sequence of the cDNA coding for the sodium/iodide symporter. In transient transfection assays this sequence exhibited promoter activity, which could be confined to nucleotides -443 to -395 relative to the ATG start codon. This minimal promot...
Citations
... High level of HDAC2 prevented apoptosis in tumour cells and inhibition of HDAC2 led to the reduction in proliferation of tumours in APC min mice [66]. HDAC2 is almost certainly regulated by APC at transcriptional level [77,78], and c-Myc is also responsible for HDAC2 expression [79]. Experimental data showed that after knockdown of c-Myc, a reduction in HDAC2 expression was observed [80]. ...
Histone deacetylases (HDACs) have been implicated in a number of diseases including cancer, cardiovascular disorders, diabetes mellitus, neurodegenerative disorders and inflammation. For the treatment of epigenetic altered diseases such as cancer, HDAC inhibitors have made a significant progress in terms of developments of isoform selective inhibition. Isoform specific HDAC inhibitors have less adverse events and better safety profile. A HDAC isoform i.e., HDAC2 demonstrated significant role in the development of variety of diseases, mainly involved in the cancer and neurodegenerative disorders. Discovery and development of selective HDAC2 inhibitors have a great potential for the treatment of target diseases. In the present compilation, we have reviewed role of HDAC2 in progression of cancer and neurodegenerative disorders, and information on the drug development opportunities for selective HDAC2 inhibition.
... Mammalian HDACs are classified into four classes (I, II, III, and IV) based on the sequence homology of the yeast histone deacetylases Rpd3 (reduced potassium dependency), Hda1 (histone deacetylase 1), HDAC1 is found in at least three evolutionally conserved, distinct protein complexes: the Sin3, the CoREST and the Mi-2/NuRD complexes (Reviewed in [2,13]). HDAC1 and HDAC2 are highly related enzymes with 82% overall sequence identity and often coexist in these complexes [14][15][16]. All complexes are recruited to target genes through interactions with DNA binding transcription factors. ...
... HDAC1 and HDAC2 often coexist in multi-component protein complexes and are highly related enzymes [14][15][16]. Interestingly, the major acetylation modifications of HDAC1 occur in the C-terminal domain, which reveals a lesser degree of homology to HDAC2. ...
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.
... The mouse HDAC2 promoter is located within Ϫ1.1 kb from the transcription start site (40). Through a comparison of mouse and human HDAC2 promoter regions, a Ϫ1.3 kb human promoter reporter was constructed to analyze the activity of human HDAC2 promoter. ...
Histone deacetylases (HDACs) that deacetylate histone and nonhistone proteins play crucial roles in a variety of cellular processes. The overexpression of HDACs is reported in many cancer types and is directly linked to accelerated cell proliferation and survival. However, little is known about how HDAC expression is regulated in cancer cells. In this study, we found that HDAC1 and HDAC2 promoters are regulated through collaborative binding of transcription factors Sp1/Sp3 and epigenetic modulators, including histone H3K4 methyltransferase SET1 and histone acetyltransferase p300, whose levels are also elevated in colon cancer cell lines and patient samples. Interestingly, Sp1 and Sp3 differentially regulate HDAC1 and HDAC2 promoter activity. In addition, Sp1/Sp3 recruits SET1 and p300 to the promoters. SET1 knockdown (KD) results in a loss of the H3K4 trimethylation mark at the promoters, as well as destabilizes p300 at the promoters. Conversely, p300 also influences SET1 recruitment and H3K4me3 level, indicating a crosstalk between p300 and SET1. Further, SET1 KD reduces Sp1 binding to the HDAC1 promoter through the increase of Sp1 acetylation. These results indicate that interactions among transcription factors and epigenetic modulators orchestrate the activation of HDAC1 and HDAC2 promoter activity in colon cancer cells.-Yang, H., Salz, T., Zajac-Kaye, M., Liao, D., Huang, S., and Qiu, Y. Overexpression of histone deacetylases in cancer cells is controlled by interplay of transcription factors and epigenetic modulators.
... The structures of the genes for Hdac1 and Hdac2 are nearly identical indicating that the two genes most probably arose from gene duplication of a common ancestor (Khier et al. 1999;Zeng et al. 1998). In contrast, the Hdac3 and Hdac8 genes have different exon/intron structures (Mahlknecht et al. 1999). ...
... Originating from a gene duplication, the genes encoding the mammalian class I histone deacetylases HDAC1 and HDAC2 show highly conserved exon-intron structures but are located on different chromosomes (Zeng et al., 1998;Khier et al., 1999). HDAC1 and HDAC2 proteins share 86% amino acid identity and associate with the same transcriptional repressor complexes, suggesting a certain functional redundancy (Brunmeir et al., 2009). ...
The histone deacetylases HDAC1 and HDAC2 are crucial regulators of chromatin structure and gene expression, thereby controlling important developmental processes. In the mouse brain, HDAC1 and HDAC2 exhibit different developmental stage- and lineage-specific expression patterns. To examine the individual contribution of these deacetylases during brain development, we deleted different combinations of Hdac1 and Hdac2 alleles in neural cells. Ablation of Hdac1 or Hdac2 by Nestin-Cre had no obvious consequences on brain development and architecture owing to compensation by the paralog. By contrast, combined deletion of Hdac1 and Hdac2 resulted in impaired chromatin structure, DNA damage, apoptosis and embryonic lethality. To dissect the individual roles of HDAC1 and HDAC2, we expressed single alleles of either Hdac1 or Hdac2 in the absence of the respective paralog in neural cells. The DNA-damage phenotype observed in double knockout brains was prevented by expression of a single allele of either Hdac1 or Hdac2. Strikingly, Hdac1(-/-)Hdac2(+/-) brains showed normal development and no obvious phenotype, whereas Hdac1(+/-)Hdac2(-/-) mice displayed impaired brain development and perinatal lethality. Hdac1(+/-)Hdac2(-/-) neural precursor cells showed reduced proliferation and premature differentiation mediated by overexpression of protein kinase C, delta, which is a direct target of HDAC2. Importantly, chemical inhibition or knockdown of protein kinase C delta was sufficient to rescue the phenotype of neural progenitor cells in vitro. Our data indicate that HDAC1 and HDAC2 have a common function in maintaining proper chromatin structures and show that HDAC2 has a unique role by controlling the fate of neural progenitors during normal brain development.
... Colon cancer is frequently associated with aberrant signaling through the Wnt pathway due to loss of both functional copies of the tumor suppressor adenomatosis polyposis coli (APC) and/or mutations in the b-catenin gene, although additional mutations are required for cancer development (Kinzler and Vogelstein, 1996). Loss of functional APC leads to overexpression of HDAC2 by a Myc-dependent mechanism; the HDAC2 promoter has a putative E-box and may be a downstream target of c-Myc (Zeng et al., 1998;Huang et al., 2005). In addition, studies demonstrate that T-cell factor (TCF)-4/Lef1-and/or the TCF-4/ Lef1-dependent Wnt pathway protein, including peroxisome proliferative activated receptor-d, induces HDAC2 transcription (He et al., 1998). ...
Epigenetic modulators, particularly histone deacetylases (HDACs), are valid targets for cancer prevention and Therapy. Recent studies report, HDAC2 overexpression associated with colon tumor progression and a potential target for colon cancer prevention. This study tested chemopreventive and dose-response effects of OSU-HDAC42, selective HDAC inhibitor, using rat colon carcinogenesis model to assess aberrant crypt foci (ACF) inhibition and familial adenomatous polyposis (FAP) model to assess intestinal tumor inhibition. Colonic ACF induced by azoxymethane (AOM) (15mg/kg BW once weekly by s.c. at 8 and 9 weeks age). One week after AOM-treatment, groups of rats were fed AIN-76A diet containing 0, 75, 150 and 300ppm OSU-HDAC42 for eight weeks, and colonic ACF were evaluated. To assess the inhibitory effect of OSU-HDAC42 on small intestinal (SI) polyps and colon tumor growth, six week-old male C57Bl/6J-APCmin/+mice were fed AIN-76A diet containing 150ppm OSU-HADC42 or 300ppm pan-HDAC inhibitor suberoylanilide hydroxyamic acid (SAHA) for 80 days. Our results demonstrate, dietary OSU-HDAC42 produced dose-dependent inhibition of AOM-induced colonic ACF formation (13-50%, P<0.01-0.0001) and reduced multiple crypt with ≥4 crypts/focus (25-57%, P<0.01-0.0001) in F344rats. 150ppm OSU-HDAC42 significantly inhibited SI polyps (>46%, P<0.001), polyps size measuring >1 mm (P<0.001) and colon tumors (>26%) in APCmin/+mice, whereas 300ppm SAHA showed non-significant inhibition. Mice fed 150ppm OSU-HDAC42 significantly decreased HDAC2, proliferating cell nuclear antigen (PCNA), B cell lymphoma 2 (Bcl2), Cyclin dependent kinase 2 (CDK2), Cell division cycle homolog25C (CDC25C) and increased p53 expression levels. These observations demonstrate, chemopreventive efficacy of OSU-HDAC42 against chemically induced and polyposis models of intestinal tumorigenesis.
... The structures of the genes for Hdac1 and Hdac2 are nearly identical indicating that the two genes most probably arose from gene duplication of a common ancestor (Khier et al. 1999;Zeng et al. 1998). In contrast, the Hdac3 and Hdac8 genes have different exon/intron structures (Mahlknecht et al. 1999). ...
The Rpd3-like members of the class I lysine deacetylase family are important regulators of chromatin structure and gene expression and have pivotal functions in the control of proliferation, differentiation and development. The highly related class I deacetylases HDAC1 and HDAC2 have partially overlapping but also isoform-specific roles in diverse biological processes, whereas HDAC3 and HDAC8 have unique functions. This review describes the role of class I KDACs in the regulation of transcription as well as their non-transcriptional functions, in particular their contributions to splicing, mitosis/meiosis, replication and DNA repair. During the past years, a number of mouse loss-of-function studies provided new insights into the individual roles of class I deacetylases in cell cycle control, differentiation and tumorigenesis. Simultaneous ablation of HDAC1 and HDAC2 or single deletion of Hdac3 severely impairs cell cycle progression in all proliferating cell types indicating that these class I deacetylases are promising targets for small molecule inhibitors as anti-tumor drugs.
... SphK2 was found in the co-repressor complexes containing class I HDACs, HDAC1 and HDAC2. Both HDAC1 and HDAC2 remove acetyl groups from histones and thus promote chromatin condensation and inhibit transcription [150,151]. Mechanistically, activated SphK2 produces S1P, which specifically binds to and inhibits HDAC1 and HDAC2, preventing histone deacetylation and, therefore, promoting transcription [12]. Nuclear SphK2 has been shown to inhibit cell proliferation [152], likely via p53independent upregulation of cyclin-dependent kinase inhibitor p21 expression [57]. ...
Sphingosine-1-phosphate (S1P) was first described as a signaling molecule over 20 years ago. Since then, great strides have been made to reveal its vital roles in vastly different cellular and disease processes. Initially, S1P was considered nothing more than the terminal point of sphingolipid metabolism; however, over the past two decades, a large number of reports have helped unveil its full potential as an important regulatory, bioactive sphingolipid metabolite. S1P has a plethora of physiological functions, due in part to its many sites of actions and its different pools, which are both intra- and extracellular. S1P plays pivotal roles in many physiological processes, including the regulation of cell growth, migration, autophagy, angiogenesis, and survival, and thus, not surprisingly, S1P has been linked to cancer. In this review, we will summarize the vast body of knowledge, highlighting the connection between S1P and cancer. We will also suggest new avenues for future research.
... As predicted ( Kacharmina et al., 2000;Miyashiro et al., 1994), GluR2 mRNA was present in these samples (Fig. 1A). To reduce the likelihood that the presence of EAAC1 mRNA was due to contamination with cell body mRNA, we tested for the presence of the cell body specific mRNA, histone deacetylase-2 (HDAC2) ( Zeng et al., 1998). Although the primers employed amplified a product of the predicted size from a control mRNA specimen (from SHSY5Y cells), no product was observed in the RNA samples generated from hippocampal dendritic aRNA samples (Fig. 1A). ...
The neuronal Na(+)-dependent glutamate transporter, excitatory amino acid carrier 1 (EAAC1, also called EAAT3), has been implicated in the control of synaptic spillover of glutamate, synaptic plasticity, and the import of cysteine for neuronal synthesis of glutathione. EAAC1 protein is observed in both perisynaptic regions of the synapse and in neuronal cell bodies. Although amino acid residues in the carboxyl terminal tail have been implicated in the dendritic targeting of EAAC1 protein, it is not known if mRNA for EAAC1 may also be targeted to dendrites. Sorting of mRNA to specific cellular domains provides a mechanism by which signals can rapidly increase translation in a local environment; this form of regulated translation has been linked to diverse biological phenomena ranging from establishment of polarity during embryogenesis to synapse development and synaptic plasticity. In the present study, EAAC1 mRNA sequences were amplified from dendritic samples that were mechanically harvested from low-density hippocampal neuronal cultures. In parallel analyses, mRNA for histone deacetylase 2 (HDAC-2) and glial fibrillary acidic protein (GFAP) was not detected, suggesting that these samples are not contaminated with cell body or glial mRNAs. EAAC1 mRNA also co-localized with Map2a (a marker of dendrites) but not Tau1 (a marker of axons) in hippocampal neuronal cultures by in situ hybridization. In control rats, EAAC1 mRNA was observed in soma and proximal dendrites of hippocampal pyramidal neurons. Following pilocarpine- or kainate-induced seizures, EAAC1 mRNA was present in CA1 pyramidal cell dendrites up to 200μm from the soma. These studies provide the first evidence that EAAC1 mRNA localizes to dendrites and suggest that dendritic targeting of EAAC1 mRNA is increased by seizure activity and may be regulated by neuronal activity/depolarization.
... Induction of HDAC2 upon loss of APC represents a novel dently induced protein such as c-Myc or PPAR␦ induces HDAC2 transcription (He et al., 1998(He et al., , 1999. Sequence analysis and mechanism for aberrant function of the HDAC-dependent transcriptional repression machinery upon genetic defects that pro-EMSA analyses of the HDAC2 promoter (Zeng et al., 1998) suggested that this could be c-Myc. Experimental evidence for mote the development of cancer. ...
Inappropriate transcriptional repression involving histone deacetylases (HDACs) is a prominent cause for the development of leukemia. We now identify faulty expression of a specific mediator of transcriptional repression in a solid tumor. Loss of the adenomatosis polyposis coli (APC) tumor suppressor induces HDAC2 expression depending on the Wnt pathway and c-Myc. Increased HDAC2 expression is found in the majority of human colon cancer explants, as well as in intestinal mucosa and polyps of APC-deficient mice. HDAC2 is required for, and sufficient on its own to prevent, apoptosis of colonic cancer cells. Interference with HDAC2 by valproic acid largely diminishes adenoma formation in APC(min) mice. These findings point toward HDAC2 as a particularly relevant potential target in cancer therapy.
