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)

In cancer, gene silencing via hypermethylation is as common as genetic mutations in p53. Understanding the relationship between mutant p53 and hypermethylation of other tumor suppressor genes is essential when elucidate mechanisms of tumor development. In this study, two isogenic human B lymphoblast cell lines with different p53 status include TK6 containing wild-type p53 and WTK1 with mutant p53 were used and contrasted. Lower levels of p16(ink4A) protein were detected in WTK1 cells than in TK6 cells, which were accompanied by increased DNA (cytosine-5)-methyltransferase 1 (DNMT1) gene expression as well as hypermethylation of the p16 ( ink4A ) promoter. siRNA experiments to transiently knock down wild-type p53 in TK6 cells resulted in increase of DNMT1 expression as well as decrease of p16(ink4A) protein. Conversely, siRNA knockdown of mutant p53 in WTK1 cells did not alter either DNMT1 or p16(ink4A) protein levels. Furthermore, loss of suppression function of mutant p53 to DNMT1 in WTK1 was caused by the attenuation of its binding ability to the DNMT1 promoter. In summary, we provide evidences to elucidate the relationship between mutant p53 and DNMT1. Our results indicate that mutant p53 loses its ability to suppress DNMT1 expression, and thus enhances methylation levels of the p16 ( ink4A ) promoter and subsequently down-regulates p16(ink4A )protein.
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PMID:DNA (cytosine-5)-methyltransferase 1 as a mediator of mutant p53-determined p16(ink4A) down-regulation. 1803 18

One of the key breakthroughs in the epigenetics/chromatin field in the last several years was the identification of enzymes capable of removing the methyl group from methylated lysines in histone proteins. Lysine-specific demethylase 1 (LSD1) was the first such enzyme identified, which has been shown to demethylate histone H3 on lysine 4 (H3K4) and lysine 9 (H3K9). LSD1 is essential for mammalian development and likely involved in many biological processes. Recent studies show that LSD1 demethylates p53 and Dnmt1 and regulates their cellular functions, indicating that LSD1 fulfills its biological functions by directly acting on both histone and non-histone proteins. LSD1 contains several defined domains and associates with a number of protein complexes. Interacting partners of LSD1 may play key roles in determining/modulating the activity and specificity of LSD1.
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PMID:LSD1 demethylates histone and non-histone proteins. 1939 67

Faithful control of cell cycle checkpoint and DNA repair contributes to prevent the cells from chromosomal instability and tumorigenesis. Dnmt1-associated protein 1 (Dmap1), a component of the NuA4 histone acetyltransferase complex, was originally identified as an interacting molecule with DNMT1 which co-localizes with PCNA at DNA replication foci. However, its role in cellular functions remains largely unknown. Here we show that Dmap1 knockdown in mouse embryonic fibroblasts (MEFs) lead to spontaneous double-strand breaks (DSBs), resulting in growth arrest because of p53-dependent cell cycle checkpoint activation. Deletion of both Dmap1 and p53 in MEFs synergized towards enhanced generation of DSBs, chromosomal abnormalities and tumor development in mice. Notably, we found that, on DNA damage, Dmap1 was recruited to the damaged sites to form complexes with gamma-H2AX and replication factors, including Pcna. Depletion of Dmap1 in MEFs abrogated the stable accumulation of Pcna at the DNA damaged sites. Furthermore, the re-introduction of Dmap1 mutants with a reduced capacity to bind Pcna failed to ameliorate the impaired DNA repair in Dmap1-depleted cells. These findings indicate that Dmap1 is required to involve Pcna in DNA repair. Together, Dmap1 plays a crucial role in DNA repair, and is indispensable for the maintenance of chromosomal integrity.
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PMID:Dmap1 plays an essential role in the maintenance of genome integrity through the DNA repair process. 1984 71

Dnmt1-associated protein 1 (Dmap1) is a core component of the NuA4 histone acetyltransferase complex and the Swr1 chromatin-remodeling complex. However, the cellular function of Dmap1 remains largely unknown. We previously reported that Dmap1 plays a crucial role in DNA repair and is indispensable for the maintenance of chromosomal integrity of mouse embryonic fibroblasts. In this study, we examined the role of Dmap1 in self-renewing HSCs. Dmap1-knockdown induced by Dmap1-specific shRNA severely compromised the proliferative capacity of HSCs in vitro and long-term repopulating capacity of HSCs in recipient mice. Dmap1-knockdown in HSCs triggered DNA damage as evident by the formation of foci of gamma-H2AX and activated p53-dependent cell cycle checkpoints. Deletion of p53 in HSCs abrogated the activation of p53-dependent cell cycle checkpoints, but did not restore the HSC function impaired by the knockdown of Dmap1. These findings suggest that Dmap1 is essential for the maintenance of genomic integrity of self-renewing HSCs and highlight DNA damage as one of the major stresses causing HSC depletion.
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PMID:Depletion of Dnmt1-associated protein 1 triggers DNA damage and compromises the proliferative capacity of hematopoietic stem cells. 2038 33

Epigenetic modifications are involved in the initiation and progression of cancer. Expression patterns and activity of DNA methyltransferases (DNMTs) are strictly controlled in normal cells, however, regulation of these enzymes is lost in cancer cells due to unknown reasons. Cancer therapies which target DNMTs are promising treatments of hematologic cancers, but they lack effectiveness in solid tumors. Solid tumors exhibit areas of hypoxia and hypoglycaemia due to their irregular and dysfunctional vasculature, and we previously showed that hypoxia reduces global DNA methylation. Colorectal carcinoma (CRC) cells (HCT116 and 379.2; p53+/+ and p53-/-, respectively) were subjected to ischemia (hypoxia and hypoglycaemia) in vitro, and levels of DNMTs were assessed. We found a significant decrease in mRNA for DNMT1, DNMT3a and DNMT3b, and similar reductions in DNMT1 and DNMT3a protein levels were detected by western blotting. In addition, total activity levels of DNMTs (as measured by an ELISA-based DNMT activity assay) were reduced in cells exposed to hypoxic and hypoglycaemic conditions. Immunofluorescence of HCT116 tumor xenografts demonstrated an inverse relationship between ischemia (as revealed by carbonic anhydrase IX staining) and DNMT1 protein. Bisulfite sequencing of the proximal promoter region of p16INK4a showed a decrease in 5-methylcytosine following in vitro exposure to ischemia. These studies provide evidence for the down-regulation of DNMTs and modulation of methylation patterns by hypoxia and hypoglycaemia in human CRC cells, both in vitro and in vivo. Our findings suggest that ischemia, either intrinsic or induced through the use of anti-angiogenic drugs, may influence epigenetic patterning and hence tumor progression.
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PMID:Ischemia dysregulates DNA methyltransferases and p16INK4a methylation in human colorectal cancer cells. 2054 77

The HPV-16 early proteins E6 and E7 are considered to function as oncoproteins in cervical cancer. DNA methyltransferase 1 (DNMT1) is one of the enzymes involved in epigenetic silencing of tumor suppressor genes. In the present study, the functional role and regulation of DNMT1 in HPV-16 E6 associated cervical cancer development were examined. Knockdown of E6 in HPV-16 positive human cervical carcinoma SiHa and CaSki cells led to the increase in p53, repression of DNMT1 protein and promoter activity. Moreover, p53 knockdown increased the DNMT1 protein as well as promoter activity, indicating that p53 may mediate E6 upregulation of DNMT1. In addition, E6 knockdown induced growth retardation in SiHa cells, and the effect was partially reverted by DNMT1 overexpression. The results suggest that HPV-16 E6 may act through p53/ DNMT1 to regulate the development of cervical cancer.
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PMID:HPV-16 E6 upregulation of DNMT1 through repression of tumor suppressor p53. 2104 57

In human pancreatic cancers, promoter CpG island hypermethylation is observed in both benign and malignant tumors. It is thought that silencing of key growth-controlling genes by promoter hypermethylation may play a role in pancreatic oncogenesis. We have shown previously that sufficient levels of DNA methyltransferase (Dnmt) 1 expression are required for the development of murine intestinal tumors. Here, we report the results of a large-scale triple cross (progeny n = 761) between Apc(Min/+), Trp53(-/-) and Dnmt1 hypomorphic mice to investigate the role of Dnmt levels in the Apc(Min/+), Trp53(-/-) mouse models of acinar cell pancreatic cancer. Mutations of both APC and TP53 are observed in human pancreatic cancer. We found that tumor burden, but not tumor size, is significantly reduced with decreasing Dnmt1 levels, suggesting that DNA methylation is involved in pancreatic tumorigenesis in this mouse model. Detailed analyses showed that the reduction in tumor burden is the result of a decrease in both early- and late-stage lesions. We observed decreased levels of DNA methylation at candidate genes in the normal pancreas of Dnmt1 hypomorphic mice. Some of these genes showed increased methylation associated with tumorigenesis, suggesting that the tumor-suppressive effects of Dnmt1 hypomorphic alleles may be mediated in part through reduced promoter hypermethylation. Our work is the first in vivo study to show the effects of reduced Dnmt levels on pancreatic tumor development.
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PMID:Reduction of pancreatic acinar cell tumor multiplicity in Dnmt1 hypomorphic mice. 2136 28

Spermatogonial stem cells (SSCs) present the potential to acquire pluripotency under specific culture conditions. However, the frequency of pluripotent cell derivation is low, and the mechanism of SSC reprogramming remains unknown. In this study, we report that induction of global DNA hypomethylation in germline stem (GS) cells (cultured SSCs) induces pluripotent cell derivation. When DNA demethylation was triggered by Dnmt1 depletion, GS cells underwent apoptosis. However, GS cells were converted into embryonic stem (ES)-like cells by double knockdown of Dnmt1 and p53. This treatment down-regulated Dmrt1, a gene involved in sexual differentiation, meiosis, and pluripotency. Dmrt1 depletion caused apoptosis of GS cells, but a combination of Dmrt1 and p53 depletion also induced pluripotency. Functional screening of putative Dmrt1 target genes revealed that Dmrt1 depletion up-regulates Sox2. Sox2 transfection up-regulated Oct4 and produced pluripotent cells. This conversion was enhanced by Oct1 depletion, suggesting that the balance of Oct proteins maintains SSC identity. These results suggest that spontaneous SSC reprogramming is caused by unstable DNA methylation and that a Dmrt1-Sox2 cascade is critical for regulating pluripotency in SSCs.
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PMID:Regulation of pluripotency in male germline stem cells by Dmrt1. 2402 16

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential regulator of DNA methylation that is highly expressed in many cancers. Here, we use transgenic zebrafish, cultured cells, and human tumors to demonstrate that UHRF1 is an oncogene. UHRF1 overexpression in zebrafish hepatocytes destabilizes and delocalizes Dnmt1 and causes DNA hypomethylation and Tp53-mediated senescence. Hepatocellular carcinoma (HCC) emerges when senescence is bypassed. tp53 mutation both alleviates senescence and accelerates tumor onset. Human HCCs recapitulate this paradigm, as UHRF1 overexpression defines a subclass of aggressive HCCs characterized by genomic instability, TP53 mutation, and abrogation of the TP53-mediated senescence program. We propose that UHRF1 overexpression is a mechanism underlying DNA hypomethylation in cancer cells and that senescence is a primary means of restricting tumorigenesis due to epigenetic disruption.
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PMID:UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. 2448 81

Neuroblastoma (NB) is a paediatric solid tumour which originates from sympathetic nervous tissues. Deletions in chromosome 1p are frequently found in unfavourable NBs and are correlated with v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) amplification; however, it remains to be elucidated how the 1p loss contributes to MYCN-related oncogenic processes in NB. In this study, we identified the role of Dnmt1-associated protein 1 (DMAP1), coded on chromosome 1p34, in the processes. We studied the expression and function of DMAP1 in NB and found that low-level expression of DMAP1 related to poor prognosis, unfavourable histology and 1p Loss of heterozygosity (LOH) of primary NB samples. Intriguingly, DMAP1 induced ataxia telangiectasia mutated (ATM) phosphorylation and focus formation in the presence of a DNA damage reagent, doxorubicin. By DMAP1 expression in NB and fibroblasts, p53 was activated in an ATM-dependent manner and p53-downstream pro-apoptotic Bcl-2 family molecules were induced at the mRNA level, resulting in p53-induced apoptotic death. BAX and p21(Cip1/Waf1) promoter activity dependent on p53 was clearly up-regulated by DMAP1. Further, MYCN transduction in MYCN single-copy NB cells accelerated doxorubicin (Doxo)-induced apoptotic cell death; MYCN is implicated in DMAP1 protein stabilisation and ATM phosphorylation in these situations. DMAP1 knockdown attenuated MYCN-dependent ATM phosphorylation and NB cell apoptosis. Together, DMAP1 appears to be a new candidate for a 1p tumour suppressor and its reduction contributes to NB tumourigenesis via inhibition of MYCN-related ATM/p53 pathway activation.
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PMID:Novel 1p tumour suppressor Dnmt1-associated protein 1 regulates MYCN/ataxia telangiectasia mutated/p53 pathway. 2455 87


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