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

Specific sites of lysine methylation on histones correlate with either activation or repression of transcription. The tumour suppressor p53 (refs 4-7) is one of only a few non-histone proteins known to be regulated by lysine methylation. Here we report a lysine methyltransferase, Smyd2, that methylates a previously unidentified site, Lys 370, in p53. This methylation site, in contrast to the known site Lys 372, is repressing to p53-mediated transcriptional regulation. Smyd2 helps to maintain low concentrations of promoter-associated p53. We show that reducing Smyd2 concentrations by short interfering RNA enhances p53-mediated apoptosis. We find that Set9-mediated methylation of Lys 372 inhibits Smyd2-mediated methylation of Lys 370, providing regulatory cross-talk between post-translational modifications. In addition, we show that the inhibitory effect of Lys 372 methylation on Lys 370 methylation is caused, in part, by blocking the interaction between p53 and Smyd2. Thus, similar to histones, p53 is subject to both activating and repressing lysine methylation. Our results also predict that Smyd2 may function as a putative oncogene by methylating p53 and repressing its tumour suppressive function.
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PMID:Repression of p53 activity by Smyd2-mediated methylation. 1710 71

The forkhead associated (FHA) domain-containing protein Smad nuclear interacting protein 1 (SNIP1) has multiple cellular functions, including the ability to interact with DNA-binding transcription factors and transcriptional coactivators. Moreover, we have demonstrated previously that SNIP1 regulates cyclin D1 expression and promoter activity. Here, we identify a new function for SNIP1 as a regulator of ATR checkpoint kinase-dependent pathways in human U-2 OS osteosarcoma cells: SNIP1 is required for p53 induction in response to ultraviolet light treatment and selectively regulates the phosphorylation of known ATR target proteins, including p53, Chk1 and the histone variant H2AX. These activities are independent of its ability to regulate cyclin D1 expression. Significantly, SNIP1 is also required for ATR-dependent functions of the human p14(ARF) tumour suppressor, including its ability to modulate the activity of the RelA(p65) NF-kappaB subunit. This, together with its other described functions, suggests that SNIP1 could have an important role during tumorigenesis and cancer therapy.
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PMID:Regulation of ATR-dependent pathways by the FHA domain containing protein SNIP1. 1726 16

Epigenetic alterations are heritable changes in gene expression without an accompanying change in primary DNA sequence. Two major mechanisms that cause epigenetic changes are post-translational histone modifications and DNA methylation at cytosine bases within a CpG dinucleotide. Epigenetic defects have turned out to be one of the most common molecular alterations in human neoplasia. Promoter hypermethylation is associated with loss of expression of tumour suppressor genes in cancer. The analysis of aberrant DNA methylation is gaining strength in the fields of cancer risk assessment, diagnosis, and therapy monitoring in different cancer types. These issues are discussed in this review.
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PMID:Cancer diagnosis, risk assessment and prediction of therapeutic response by means of DNA methylation markers. 1732 28

Despite the completion of the Human Genome Project, we are still far from understanding the molecular events underlying epigenetic change in cancer. Cancer is a disease of the DNA with both genetic and epigenetic changes contributing to changes in gene expression. Epigenetics involves the interplay between DNA methylation, histone modifications and expression of non-coding RNAs in the regulation of gene transcription. We now know that tumour suppressor genes, with CpG island-associated promoters, are commonly hypermethylated and silenced in cancer, but we do not understood what triggers this process or when it occurs during carcinogenesis. Epigenetic gene silencing has always been envisaged as a local event silencing discrete genes, but recent data now indicates that large regions of chromosomes can be co-coordinately suppressed; a process termed long range epigenetic silencing (LRES). LRES can span megabases of DNA and involves broad heterochromatin formation accompanied by hypermethylation of clusters of contiguous CpG islands within the region. It is not clear if LRES is initiated by one critical gene target that spreads and conscripts innocent bystanders, analogous to large genetic deletions or if coordinate silencing of multiple genes is important in carcinogenesis? Over the next decade with the exciting new genomic approaches to epigenome analysis and the initiation of a Human Epigenome Project, we will understand more about the interplay between DNA methylation and chromatin modifications and the expression of non-coding RNAs, promising a new range of molecular diagnostic cancer markers and molecular targets for cancer epigenetic therapy.
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PMID:Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis. 1761 53

p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation. Histone lysine methylation has recently been shown to be reversible; however, it is not known whether non-histone proteins are substrates for demethylation. Here we show that, in human cells, the histone lysine-specific demethylase LSD1 (refs 3, 4) interacts with p53 to repress p53-mediated transcriptional activation and to inhibit the role of p53 in promoting apoptosis. We find that, in vitro, LSD1 removes both monomethylation (K370me1) and dimethylation (K370me2) at K370, a previously identified Smyd2-dependent monomethylation site. However, in vivo, LSD1 shows a strong preference to reverse K370me2, which is performed by a distinct, but unknown, methyltransferase. Our results indicate that K370me2 has a different role in regulating p53 from that of K370me1: K370me1 represses p53 function, whereas K370me2 promotes association with the coactivator 53BP1 (p53-binding protein 1) through tandem Tudor domains in 53BP1. Further, LSD1 represses p53 function through the inhibition of interaction of p53 with 53BP1. These observations show that p53 is dynamically regulated by lysine methylation and demethylation and that the methylation status at a single lysine residue confers distinct regulatory output. Lysine methylation therefore provides similar regulatory complexity for non-histone proteins and for histones.
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PMID:p53 is regulated by the lysine demethylase LSD1. 1780 99

Inverted CCAAT box-binding protein of 90 kDa (ICBP90) is over-expressed in several types of cancer, including breast, prostate and lung cancers. In search for proteins that interact with the set and ring-associated (SRA) domain of ICBP90, we used the two-hybrid system and screened a placental cDNA library. Several clones coding for a new domain of DNMT1 were found. The interaction, between the ICBP90 SRA domain and the DNMT1 domain, has been confirmed with purified proteins by glutathione-S-transferase pull-down experiments. We checked whether ICBP90 and DNMT1 are present in the same macro-molecular complexes in Jurkat cells and immortalized human vascular smooth muscle cells (HVTs-SM1). Co-immunoprecipitation experiments showed that ICBP90 and DNMT1 are present in the same molecular complex, which was further confirmed by co-localization experiments as assessed by immunocytochemistry. Downregulation of ICBP90 and DNMT1 decreased VEGF gene expression, a major pro-angiogenic factor, whereas those of p16(INK4A) gene and RB1 gene were significantly enhanced. Together, these results indicate that DNMT1 and ICBP90 are involved in VEGF gene expression, possibly via an interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 and an upregulation of p16(INK4A). They further suggest a new role of ICBP90 in the relationship between histone ubiquitination and DNA methylation in the context of tumoral angiogenesis and tumour suppressor genes silencing.
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PMID:The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. 1793 16

Human colon carcinoma cells (HCT116) differing in p53 status were exposed to benzo(a)pyrene (BaP) or anti-benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide (BPDE) and their gene expression responses compared by complementary DNA microarray technology. Exposure of cells to BPDE for up to 24 h resulted in gene expression profiles more distinguishable by duration of exposure than by p53 status, although a subset of genes were identified that had significantly different expression in p53 wild-type (WT) cells relative to p53-null cells. Apoptotic signalling genes were up-regulated in p53-WT cells but not in p53-null cells and, consistent with this, reduced viability and caspase activity were also p53 dependent. BPDE modulated cell cycle and histone genes in both cell lines and, in agreement with this, both cell lines accumulated in S phase. In p53-WT cells, G(2) arrest was also evident, which was associated with accumulation of CDKN1A. Regardless of p53 status, exposure to BaP for up to 48 h had subtle effects on gene transcription and had no influence on cell viability or cell cycle. Interestingly, DNA adduct formation after BaP, but not BPDE, exposure was p53 dependent with 10-fold lower levels detected in p53-null cells. Other cell lines were investigated for BaP-DNA adduct formation and in these the effect of p53 knockdown was also to reduce adduct formation. Taken together, these results give further insight into the role of p53 in the response of human cells to BaP and BPDE and suggest that loss of this tumour suppressor can influence the metabolic activation of BaP.
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PMID:Identification through microarray gene expression analysis of cellular responses to benzo(a)pyrene and its diol-epoxide that are dependent or independent of p53. 1794 61

The CDX2 and CDX1 homeobox genes have respectively a tumour suppressor and proliferative role in the intestinal epithelium. We analyzed DNA methylation and histones modifications associated with CDX2 and CDX1 promoters in two human colon cancer cell lines expressing differentially these genes, Caco2/TC7 [CDX2 positive-CDX1 negative] and HT29 [CDX2 negative-CDX1 negative] cells. Chromatin immunoprecipitation experiments indicated that CDX2 and CDX1 gene expression correlated with a histone modifications pattern characterizing active chromatin (H3K4 trimethylated and H3 acetylated). Bisulfite DNA sequencing and methylation-specific PCR showed that CDX2 and CDX1 promoters display no methylation in HT29 cells even though both genes are not expressed. In contrast, the CDX1 promoter is methylated in Caco2/TC7. DNA demethylation by 5aza-dC or the combination of 5aza-dC plus SAHA, an inhibitor of histone deacetylases, restored CDX1 expression in Caco2/TC7 cells but these treatments were inefficient on both CDX2 and CDX1 in HT29 cells. Thus, in colon cancer cells the changes in chromatin conformation are heterogeneous and repression of CDX2 and CDX1 in HT29 cells is not due to epigenetic mechanisms. In vivo, dietary deprivation of methyl groups in rats upregulated CDX1 mRNA and downregulated to a lesser extent CDX2 mRNA expression. Moreover, methyl group deprivation downregulated CDX2 protein by changing its phosphorylation pattern. The changes in CDX2 and CDX1 expression determined by methyl group deprivation may constitute one of the mechanisms sustaining the protective role attributed to folate in colon cancer.
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PMID:Differential regulation of CDX1 and CDX2 gene expression by deficiency in methyl group donors. 1818 48

SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation; we and others previously found that SIRT1 promotes cell survival by deacetylating p53 (refs 4-6). These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice. Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53-independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1alpha directly modulate metabolic responses. These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1-mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference (RNAi) stimulates SIRT1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1.
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PMID:Negative regulation of the deacetylase SIRT1 by DBC1. 1823 2

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


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