Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Methylcytosine residues in the DNA (DNA methylation) are formed from the transfer of the methyl group from S-adenosylmethionine to the C-5 position of cytosine by the DNA-(cytosine-5) methyltransferases (DNMTs). Although regional hypermethylation and global hypomethylation of the genome are commonly observed in neoplastic cells, how these aberrant methylation patterns occur remains unestablished. We report here that sulfonate-derived methylating agents, unlike N-methylnitrosourea or iodomethane, are potent in depleting DNMT1 proteins in human cells, in addition to their DNA-damaging properties. Their effects on cellular DNMT1 are time and dosage dependent but independent of cell type. Unlike gamma-irradiation, these agents apparently do not activate the p53/p21(WAF1) DNA damage response pathway to deplete the DNMT1 proteins because cells with wild-type, mutated, or inactivated p53 behave similarly. However, cell cycle analysis and protease assay studies strongly suggest that methylmethanesulfonate may activate a cellular protease to degrade DNMT1. These results explain why reported observations on the effect of alkylating agents on DNMT1 activities in human cells vary significantly and provide a crucial link to understand the mechanism behind genomic hypomethylation.
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PMID:Selective depletion of human DNA-methyltransferase DNMT1 proteins by sulfonate-derived methylating agents. 1191 26

Uteroplacental insufficiency causes intrauterine growth retardation (IUGR), which is associated with adult onset diseases such as hypertension. Previous studies demonstrate that growth retardation in humans and rats decreases glomeruli number; however, the molecular mechanisms responsible for this reduction are unknown. Apoptosis plays a key role in renal organogenesis. We therefore hypothesized that the in utero deprivation associated with uteroplacental insufficiency decreases glomeruli, increases apoptosis, and alters the mRNA levels of key apoptosis-related proteins in full-term IUGR kidneys. To prove this hypothesis, we induced asymmetric IUGR through bilateral uterine artery ligation of the pregnant rat. We found that uteroplacental insufficiency significantly reduced glomeruli number while increasing TUNEL staining and caspase-3 activity in the IUGR kidney. A significant decrease in Bcl-2 mRNA and a significant increase in Bax and p53 mRNA further characterized the IUGR kidney. Because altered p53 CpG methylation affects p53 expression, we analyzed p53 promoter CpG methylation using methylation-sensitive restriction enzymes and real-time PCR. Uteroplacental insufficiency specifically decreased CpG methylation of the renal p53 BstU I site promoter without affecting the Hha I or the Aci I sites. Uteroplacental insufficiency also induced a relative hypomethylation from exon 5 to exon 8, which was associated with deceased mRNA levels of DNMT1. We conclude that uteroplacental insufficiency alters p53 DNA CpG methylation, affects mRNA levels of key apoptosis-related proteins, increases renal apoptosis, and reduces glomeruli number in the IUGR kidney. We speculate that these changes represent mechanisms that contribute to the fetal origins of adult disease.
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PMID:Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney. 1455 30

We have generated two lentiviral vectors for conditional, Cre-lox-regulated, RNA interference. One vector allows for conditional activation, whereas the other permits conditional inactivation of short hairpin RNA (shRNA) expression. The former is based on a strategy in which the mouse U6 promoter has been modified by including a hybrid between a LoxP site and a TATA box. The ability to efficiently control shRNA expression by using these vectors was shown in cell-based experiments by knocking down p53, nucleophosmin and DNA methyltransferase 1. We also demonstrate the usefulness of this approach to achieve conditional, tissue-specific RNA interference in Cre-expressing transgenic mice. Combined with the growing array of Cre expression strategies, these vectors allow spatial and temporal control of shRNA expression in vivo and should facilitate functional genetic analysis in mammals.
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PMID:Cre-lox-regulated conditional RNA interference from transgenes. 1524 Aug 89

Methyltransferase inhibitors commonly used in clinical trials promote tumor cell death, but their detailed cytotoxic action is not yet fully understood. A deeper knowledge about their apotosis-inducing mechanisms and their interaction with DNA methyltransferases (DNMTs) DNMT1, DNMT3a, and DNMT3b might allow the design of more effective drugs with lower cytotoxicity. 5-aza-cytidine (5-aza-CR), a potent inhibitor of DNMT1, is known to induce demethylation and reactivation of silenced genes. In this study, we investigated the p53 dependence of apoptotic, cell cycle, and growth inhibitory effects of 5-aza-CR, as well as the influence on the expression level of DNMT1, DNMT3a, and DNMT3b in the colon cancer cell line HCT-116. Exposure to 5-aza-CR induced the up-regulation of genes promoting cell cycle arrest and DNA repair (p21(WAF1) and GADD45) or apoptosis (p53, RIPK2, Bak1, caspase 5, and caspase 6). In parallel, there was a down-regulation of antiapoptotic Bcl2 protein and the G(2)/M-mediator cyclin B1. Co-incubation with pifithrin-alpha (PFT-alpha), a selective p53 inhibitor, restored GADD45, Bcl2, cyclin B1, and p21(WAF1) expression levels and almost completely reversed the growth inhibitory, cell cycle, and apoptotic effects of 5-aza-CR. 5-aza-CR treatment caused global demethylation and reactivation of p16(INK4) expression. There was a marked decrease in DNMT1 and DNMT3a mRNA expression, with PFT-alpha reversing these effects. However, 5-aza-CR treatment did not modulate DNMT3b expression. Our data demonstrate that 5-aza-CR action in HCT-116 is mediated by p53 and its downstream effectors p21(WAF1) and GADD45. This is the first report to show a link between p53 and regulation of DNMT1 and de novo methyltransferase DNMT3a.
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PMID:5-Aza-cytidine is a potent inhibitor of DNA methyltransferase 3a and induces apoptosis in HCT-116 colon cancer cells via Gadd45- and p53-dependent mechanisms. 2758 47

DNA (cytosine-5)-methyltransferase (DNMT) 1 participates in transcriptional repression of genes by methylation-dependent and -independent mechanisms. Here, DNMT1 is shown to bind p53 and colocalize in the nucleus. DNMT1-mediated methylation is stimulated by p53 in vitro. Upon p53 induction, a reporter construct containing the antiapoptotic gene survivin promoter, which contains a natural p53 binding site, was methylated in WT HCT116 cells but not in DNMT1 null or p53 null cells. Endogenous survivin gene repression involves cooperation between DNMT1 and p53 and is relieved by introduction of DNMT1- or p53-specific small inhibitory RNA. DNMT1 null cells did not exhibit a significant repressive effect for p53 responsive survivin and cdc25C gene expression compared with the parental cells. Normal human fibroblasts also exhibited similar DNMT1- and p53-mediated methylation of the survivin promoter, suggesting cooperation between p53 and DNMT1 in gene silencing.
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PMID:Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. 1565 47

Recent studies using hypomorphic DNA methyltransferase 1 (DNMT1) alleles have suggested that strategies aiming to reduce DNA methylation may increase genomic instability and lymphomagenesis. Given our recent finding that loss of methyl-binding domain protein 2 (Mbd2) suppresses intestinal tumorigenesis, we have tested whether loss of Mbd2 increases lymphomagenesis by intercrossing Mbd2 deficient mice with p53 deficient and p53 heterozygous mice. Unlike DNMT1, loss of Mbd2 does not accelerate lymphomagenesis, arguing that MBD2 may represent a better potential therapeutic target than DNMT1.
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PMID:MBD2 deficiency does not accelerate p53 mediated lymphomagenesis. 1573 63

Aberrant DNA methylation and increased expression of DNA methyltransferases (DNMTs) are features of tumor cells. To investigate roles for DNMTs during hepatocarcinogenesis, we examined DNMT expression at both the mRNA and protein level in hepatocellular carcinomas (HCCs) and paired non-neoplastic liver tissues, along with measuring the DNA methylation status of five tumor suppressor genes. Expression of DNMT1, DNMT3a and DNMT3b mRNA was detected in 33.3, 59.3, and 55.6% of HCCs and 40.7, 22.2, and 0% of non-neoplastic liver tissues, respectively. DNMT1 and DNMT3a were immunoreactive in 100 and 48% of HCCs and 52 and 0% of non-neoplastic liver tissues. The DNMT3a mRNA expression profile showed significant correlation with its immunoreactivity (P=0.022). DNA methylation status of five tumor suppressor genes, HIC-1, p16, RASSF1A, p53, and RB1 was detected in 85.2, 48.1, 44.4, 22.2, and 0% of HCCs, respectively. There was no significant correlation between DNMT mRNA expression and DNA methylation (P>0.05). DNMT immunoreactivity was also not associated with DNA methylation except HIC-1 (P=0.036) and p53 methylation (P=0.009). Despite the lack of correlation between DNA methylation status and DNMT expression, the frequency of hypermethylation of tumor suppressor genes remained relatively high in HCCs, suggesting that regional DNA hypermethylation is involved in hepatocarcinogenesis and that there may be other mechanisms for increasing DNA methylation.
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PMID:DNA methyltransferase expression and DNA hypermethylation in human hepatocellular carcinoma. 1588 82

A strong association exists between states of chronic inflammation and cancer, and it is believed that mediators of inflammation may be responsible for this phenomenon. Interleukin 6 (IL-6) is an inflammatory cytokine known to play a role in the growth and survival of many types of tumors, yet the mechanisms employed by this pleomorphic cytokine to accomplish this feat are still poorly understood. Another important factor in tumor development seems to be the hypermethylation of CpG islands located within the promoter regions of tumor suppressor genes. This common epigenetic alteration enables tumor cells to reduce or inactivate the expression of important tumor suppressor and cell cycle regulatory genes. Here we show that in the IL-6-responsive human multiple myeloma cell line KAS 6/1, the promoter region of p53 is epigenetically modified by methyltransferases, resulting in decreased levels of expression. Furthermore, cells treated with IL-6 exhibit an increase in the expression of the DNA maintenance methylation enzyme, DNMT-1. The DNA methyltransferase inhibitor zebularine reverses the methylation of the p53 promoter, allowing the resumption of its expression. However, when zebularine is withdrawn from the cells, the reestablishment of the original CpG island methylation within the p53 promoter does not occur in the absence of IL-6, and cells which do not receive IL-6 eventually die, as p53 expression continues unchecked by remethylation. Interestingly, this loss of viability seems to involve not the withdrawal of cytokine, but the inability of the cell to resilence the promoter. Consistent with this model, when cells that express IL-6 in an autocrine fashion are subjected to identical treatment, p53 expression is reduced shortly after withdrawal of zebularine. Therefore, it seems IL-6 is capable of maintaining promoter methylation thus representing one of the possible mechanisms used by inflammatory mediators in the growth and survival of tumors.
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PMID:Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. 1681 68

It has been reported that genomic DNA methylation decreases gradually during cell culture and an organism's aging. However, less is known about the methylation changes of age-related specific genes in aging. p21(Waf1/Cip1) and p16(INK4a) are cyclin-dependent kinase (Cdk) inhibitors that are critical for the replicative senescence of normal cells. In this study, we show that p21(Waf1/Cip1) and p16(INK4a) have different methylation patterns during the aging process of normal human 2BS and WI-38 fibroblasts. p21(Waf1/Cip1) promoter is gradually methylated up into middle-aged fibroblasts but not with senescent fibroblasts, whereas p16(INK4a) is always unmethylated in the aging process. Correspondently, the protein levels of DNA methyltransferase 1 (DNMT1) and DNMT3a increase from young to middle-aged fibroblasts but decrease in the senescent fibroblasts, while DNMT3b decreases stably from young to senescent fibroblasts. p21(Waf1/Cip1) promoter methylation directly represses its expression and blocks the radiation-induced DNA damage-signaling pathway by p53 in middle-aged fibroblasts. More importantly, demethylation by 5-aza-CdR or DNMT1 RNA interference (RNAi) resulted in an increased p21(Waf1/Cip1) level and premature senescence of middle-aged fibroblasts demonstrated by cell growth arrest and high beta-Galactosidase expression. Our results suggest that p21(Waf1/Cip1) but not p16(INK4a) is involved in the DNA methylation mediated aging process. p21(Waf1/Cip1) promoter methylation may be a critical biological barrier to postpone the aging process.
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PMID:p21Waf1/Cip1 plays a critical role in modulating senescence through changes of DNA methylation. 1651 63

Drug development in human chronic lymphocytic leukemia (CLL) has been limited by lack of a suitable animal model to adequately assess pharmacologic properties relevant to clinical application. A recently described TCL-1 transgenic mouse develops a chronic B-cell CD5(+) leukemia that might be useful for such studies. Following confirmation of the natural history of this leukemia in the transgenic mice, we demonstrated that the transformed murine lymphocytes express relevant therapeutic targets (Bcl-2, Mcl-1, AKT, PDK1, and DNMT1), wild-type p53 status, and in vitro sensitivity to therapeutic agents relevant to the treatment of human CLL. We then demonstrated the in vivo clinical activity of low-dose fludarabine in transgenic TCL-1 mice with active leukemia. These studies demonstrated both early reduction in blood-lymphocyte count and spleen size and prolongation of survival (P = .046) compared with control mice. Similar to human CLL, an emergence of resistance was noted with fludarabine treatment in vivo. Overall, these studies suggest that the TCL-1 transgenic leukemia mouse model has similar clinical and therapeutic response properties to human CLL and may therefore serve as a useful in vivo tool to screen new drugs for subsequent development in CLL.
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PMID:Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. 1667 Feb 63


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