Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone acetylation appears to play an important role in transcriptional regulation. Inactivation of chromatin by histone deacetylation is involved in the transcriptional repression of several tumour suppressor genes, including p21(WAF1/CIP1). However, the in vivo status of histone acetylation in human cancers, including gastric carcinoma, is not well understood. This study shows that histone H3 in the p21(WAF1/CIP1) promoter region is hypoacetylated and that this hypoacetylation is associated with reduced p21(WAF1/CIP1) expression in gastric carcinoma specimens. Chromatin immunoprecipitation assays revealed that histone H3 was hypoacetylated in the p21(WAF1/CIP1) promoter and coding regions in 10 (34.5%) and 10 (34.5%) of 29 gastric carcinoma specimens, respectively. Hypoacetylation of histone H4 in the p21(WAF1/CIP1) promoter and coding regions was observed in 6 (20.7%) and 16 (55.2%) of 29 gastric carcinoma specimens, respectively. p21(WAF1/CIP1) mRNA levels were associated with histone H3 acetylation status in the p21(WAF1/CIP1) promoter region (p = 0.047) but not p53 mutation status (p = 0.460). In gastric carcinoma cell lines, expression of p21(WAF1/CIP1) protein was induced by trichostatin A, a histone deacetylase inhibitor. This induction was associated with hyperacetylation of histone H3 in the p21(WAF1/CIP1) promoter region. Hyperacetylation of histone H4 in the p21(WAF1/CIP1) promoter region did not appear to be associated with increased expression. Induction of p21(WAF1/CIP1) protein expression was associated with hyperacetylation of histones H3 and H4 in the p21(WAF1/CIP1) coding region. Expression of a dominant-negative mutant of p53 reduced expression of p21(WAF1/CIP1) protein. Histone H4 acetylation in both the promoter and coding regions of the p21(WAF1/CIP1) gene in cells expressing dominant-negative p53 was less than half of that in cells expressing wild-type p53, whereas histone H3 acetylation in both the promoter and coding regions was slightly reduced (by approximately 20%) in cells expressing the dominant-negative p53. These findings provide evidence that alteration of histone acetylation occurs in human cancer tissue specimens such as those from gastric carcinoma.
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PMID:Histone H3 acetylation is associated with reduced p21(WAF1/CIP1) expression by gastric carcinoma. 1558 62

As combinations of genetic and/or epigenetic alterations occurring during salivary gland carcinogenesis are largely unknown, we here analyzed 36 salivary gland carcinomas (SGCs) for changes in INK4a/ARF, RB1, p21, p27, PTEN, p53, MDM2 and O6-MGMT genes using methylation specific PCR (MSP), loss of heterozygosity (LOH) assays and mutational analysis with immunohistochemistry (IHC), as well as histone H3 and H4 acetylation status. The RB1 gene was found to be the most frequently methylated (41.7% of cases), while methylation of p27(Kip1) and O6-MGMT were less frequent 8.3% and 5.6%, respectively). Two other genes, p21(Waf1) and PTEN, were unmethylated in the SGCs examined. RB1 methylation significantly correlated with loss of expression as determined by IHC (P=0.03), and also a poor prognosis (P=0.02). p53 mutations were found in 8 cases (22.2%), coupled with p14ARF hypermethylation in two cases. LOH in INK4a/ARF and the RB1 locus was observed in 33.3% and 28.6% of the lesions, respectively. There was no correlation between 9p21 LOH and methylation of the INK4a/ARF gene. Promoter hypermethylation of RB1 coupled with LOH was evident in three samples immuno-negative for RB1. Acetylation of histone H3 and H4 was detected in 6 and 5 cases, respectively. These findings indicate that epigenetic silencing of tumour suppressor genes via promoter hypermethylation might be crucial for salivary gland carcinogenesis, particularly in the RB1 gene. Thus epigenetic events including methylation and acetylation as well as genetic alterations may have important contributions.
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PMID:Genetic and epigenetic alteration profiles for multiple genes in salivary gland carcinomas. 1569 18

Acute induction of oncogenic Ras provokes cellular senescence involving the retinoblastoma (Rb) pathway, but the tumour suppressive potential of senescence in vivo remains elusive. Recently, Rb-mediated silencing of growth-promoting genes by heterochromatin formation associated with methylation of histone H3 lysine 9 (H3K9me) was identified as a critical feature of cellular senescence, which may depend on the histone methyltransferase Suv39h1. Here we show that Emicro-N-Ras transgenic mice harbouring targeted heterozygous lesions at the Suv39h1, or the p53 locus for comparison, succumb to invasive T-cell lymphomas that lack expression of Suv39h1 or p53, respectively. By contrast, most N-Ras-transgenic wild-type ('control') animals develop a non-lymphoid neoplasia significantly later. Proliferation of primary lymphocytes is directly stalled by a Suv39h1-dependent, H3K9me-related senescent growth arrest in response to oncogenic Ras, thereby cancelling lymphomagenesis at an initial step. Suv39h1-deficient lymphoma cells grow rapidly but, unlike p53-deficient cells, remain highly susceptible to adriamycin-induced apoptosis. In contrast, only control, but not Suv39h1-deficient or p53-deficient, lymphomas senesce after drug therapy when apoptosis is blocked. These results identify H3K9me-mediated senescence as a novel Suv39h1-dependent tumour suppressor mechanism whose inactivation permits the formation of aggressive but apoptosis-competent lymphomas in response to oncogenic Ras.
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PMID:Oncogene-induced senescence as an initial barrier in lymphoma development. 1607 29

Dynamic regulation of diverse nuclear processes is intimately linked to covalent modifications of chromatin. Much attention has focused on methylation at lysine 4 of histone H3 (H3K4), owing to its association with euchromatic genomic regions. H3K4 can be mono-, di- or tri-methylated. Trimethylated H3K4 (H3K4me3) is preferentially detected at active genes, and is proposed to promote gene expression through recognition by transcription-activating effector molecules. Here we identify a novel class of methylated H3K4 effector domains--the PHD domains of the ING (for inhibitor of growth) family of tumour suppressor proteins. The ING PHD domains are specific and highly robust binding modules for H3K4me3 and H3K4me2. ING2, a native subunit of a repressive mSin3a-HDAC1 histone deacetylase complex, binds with high affinity to the trimethylated species. In response to DNA damage, recognition of H3K4me3 by the ING2 PHD domain stabilizes the mSin3a-HDAC1 complex at the promoters of proliferation genes. This pathway constitutes a new mechanism by which H3K4me3 functions in active gene repression. Furthermore, ING2 modulates cellular responses to genotoxic insults, and these functions are critically dependent on ING2 interaction with H3K4me3. Together, our findings establish a pivotal role for trimethylation of H3K4 in gene repression and, potentially, tumour suppressor mechanisms.
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PMID:ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. 1682 38

Covalent modifications of histone tails have a key role in regulating chromatin structure and controlling transcriptional activity. In eukaryotes, histone H3 trimethylated at lysine 4 (H3K4me3) is associated with active chromatin and gene expression. We recently found that plant homeodomain (PHD) finger of tumour suppressor ING2 (inhibitor of growth 2) binds H3K4me3 and represents a new family of modules that target this epigenetic mark. The molecular mechanism of H3K4me3 recognition, however, remains unknown. Here we report a 2.0 A resolution structure of the mouse ING2 PHD finger in complex with a histone H3 peptide trimethylated at lysine 4. The H3K4me3 tail is bound in an extended conformation in a deep and extensive binding site consisting of elements that are conserved among the ING family of proteins. The trimethylammonium group of Lys 4 is recognized by the aromatic side chains of Y215 and W238 residues, whereas the intermolecular hydrogen-bonding and complementary surface interactions, involving Ala 1, Arg 2, Thr 3 and Thr 6 of the peptide, account for the PHD finger's high specificity and affinity. Substitution of the binding site residues disrupts H3K4me3 interaction in vitro and impairs the ability of ING2 to induce apoptosis in vivo. Strong binding of other ING and YNG PHD fingers suggests that the recognition of H3K4me3 histone code is a general feature of the ING/YNG proteins. Elucidation of the mechanisms underlying this novel function of PHD fingers provides a basis for deciphering the role of the ING family of tumour suppressors in chromatin regulation and signalling.
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PMID:Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. 1682 38

HOXA5 is a member of the HOX gene family, which is known to play key roles during embryonic development and in differentiation of adult cells. In addition, HOXA5 has been implicated as a tumour suppressor in breast cancer and shown to transactivate the p53 gene. CpG island methylation is a common mechanism of gene inactivation in tumour cells, but is rarely involved in control of cell-type-specific (CTS) expression in normal cells. However, here we demonstrate that HOXA5 is one of a small number of genes whose CTS expression pattern is controlled by CTS CpG island methylation in normal cells. Furthermore, chromatin immunoprecipitation analysis identified novel patterns of histone modifications associated with DNA methylation of HOXA5. High levels of methylation of histone residues (lysine 9 and 36 of histone H3) previously associated with transcriptional repression were present in the unmethylated, actively transcribing state, and were then reduced following DNA methylation and gene inactivation. Alterations to the normal patterns of HOXA5 gene methylation were also observed in tumour cells. Quantitative analysis of HOXA5 methylation identified the presence of limited methylation in all of the breast, lung and ovarian tumours examined. However, methylation levels in these three tumour types were nearly always low and comparable with that detected in the corresponding normal tissue. In contrast, acute myeloid leukaemia (AML) samples frequently (60% of samples) exhibited very high methylation levels, far greater than that seen in normal haematopoietic cells, suggesting a role for hypermethylation of HOXA5 in the development of AML, consistent with its previously identified role in haematopoietic differentiation.
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PMID:HOXA5 is targeted by cell-type-specific CpG island methylation in normal cells and during the development of acute myeloid leukaemia. 1686 Dec 63

JHDM1B is an evolutionarily conserved and ubiquitously expressed member of the JHDM (JmjC-domain-containing histone demethylase) family. Because it contains an F-box motif, this protein is also known as FBXL10 (ref. 4). With the use of a genome-wide RNAi screen, the JHDM1B worm orthologue (T26A5.5) was identified as a gene that regulates growth. In the mouse, four independent screens have identified JHDM1B as a putative tumour suppressor by retroviral insertion analysis. Here we identify human JHDM1B as a nucleolar protein and show that JHDM1B preferentially binds the transcribed region of ribosomal DNA to repress the transcription of ribosomal RNA genes. We also show that repression of ribosomal RNA genes by JHDM1B is dependent on its JmjC domain, which is necessary for the specific demethylation of trimethylated lysine 4 on histone H3 in the nucleolus. In agreement with the notion that ribosomal RNA synthesis and cell growth are coupled processes, we show a JmjC-domain-dependent negative effect of JHDM1B on cell size and cell proliferation. Because aberrant ribosome biogenesis and the disruption of epigenetic control mechanisms contribute to cellular transformation, these results, together with the low levels of JHDM1B expression found in aggressive brain tumours, suggest a role for JHDM1B in cancer development.
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PMID:JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes. 1799 99

The frequency of oesophageal adenocarcinoma is increasing in Western countries for unknown reasons, and correlates with a corresponding increase in the pre-malignant condition, Barrett's Oesophagus, which raises the risk of adenocarcinoma by some 40- to 125-fold. We have examined how disease progression correlates with changes in expression of the p14ARF (ARF) tumour suppressor, a key regulator of the p53 tumour suppressor pathway that is silenced in some 30% of cancers overall, but for which a role in oesophageal cancer is unclear. We have used quantitative PCR, RT-PCR, methylation-specific PCR and chromatin-immunoprecipitation to examine the regulation and function of ARF in oesophageal adenocarcinoma tissue specimens and cell lines. We find highly significant reductions (P< 0.001) in ARF expression during disease progression from normal oesophageal epithelium to Barrett's Oesophagus to adenocarcinoma, with 57/76 (75%) adenocarcinomas displaying undetectable levels of ARF expression. Retention of ARF expression in adenocarcinoma is a highly significant indicator of increased survival (P< 0.001) and outperforms all clinical variables in a multivariate model. CpG methylation as well as histone H3 methylation of lysines 9 and 27 contribute independently to ARF gene silencing in adenocarcinoma cell lines and can be reversed by 5-aza-2'-deoxycytidine. The results suggest that silencing of ARF is involved in the pathogenesis of oesophageal adenocarcinoma and show that either DNA or histone methylation can provide the primary mechanism for ARF gene silencing. Silencing of ARF could provide a useful marker for increased risk of progression and poor prognosis.
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PMID:Progressive silencing of p14ARF in oesophageal adenocarcinoma. 1841 May 30

Multiple endocrine neoplasia type 1 (MEN1) is caused by inactivating germ line mutations of the MEN1 tumour suppressor gene. The MEN1 gene product, menin, participates in many cellular processes, including regulation of gene transcription. As part of a protein complex that writes a trimethyl mark on lysine 4 of histone H3 (H3K4me3), menin is involved in activating gene transcription. Several functions of the menin histone methyltransferase complex have been discovered through protein interaction studies. Menin can interact with nuclear receptors and regulate transcription of hormone responsive target genes. Menin regulates transcription of cyclin-dependent kinase inhibitor and Hox genes via the chromatin-associated factor LEDGF. Aberrant expression of menin target genes in tumours in MEN1 patients suggests that loss of writing of the H3K4me3 mark contributes to MEN1 tumourigenesis. At present, drugs are being developed that target chromatin modifications. The identification of compounds that could restore H3K4me3 on menin target genes would provide new therapeutic strategies for MEN1 patients.
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PMID:Multiple endocrine neoplasia type 1: a chromatin writer's block. 1952 25

In human B cells infected with Epstein-Barr virus (EBV), latency-associated virus gene products inhibit expression of the pro-apoptotic Bcl-2-family member Bim and enhance cell survival. This involves the activities of the EBV nuclear proteins EBNA3A and EBNA3C and appears to be predominantly directed at regulating Bim mRNA synthesis, although post-transcriptional regulation of Bim has been reported. Here we show that protein and RNA stability make little or no contribution to the EBV-associated repression of Bim in latently infected B cells. However, treatment of cells with inhibitors of histone deacetylase (HDAC) and DNA methyltransferase (DNMT) enzymes indicated that epigenetic mechanisms are involved in the down-regulation of Bim. This was initially confirmed by chromatin immunoprecipitation analysis of histone acetylation levels on the Bim promoter. Consistent with this, methylation-specific PCR (MSP) and bisulphite sequencing of regions within the large CpG island located at the 5' end of Bim revealed significant methylation of CpG dinucleotides in all EBV-positive, but not EBV-negative B cells examined. Genomic DNA samples exhibiting methylation of the Bim promoter included extracts from a series of explanted EBV-positive Burkitt's lymphoma (BL) biopsies. Subsequent analyses of the histone modification H3K27-Me3 (trimethylation of histone H3 lysine 27) and CpG methylation at loci throughout the Bim promoter suggest that in EBV-positive B cells repression of Bim is initially associated with this repressive epigenetic histone mark gradually followed by DNA methylation at CpG dinucleotides. We conclude that latent EBV initiates a chain of events that leads to epigenetic repression of the tumour suppressor gene Bim in infected B cells and their progeny. This reprogramming of B cells could have important implications for our understanding of EBV persistence and the pathogenesis of EBV-associated disease, in particular BL.
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PMID:Epstein-barr virus latency in B cells leads to epigenetic repression and CpG methylation of the tumour suppressor gene Bim. 1955 59


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