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

Loss of the of the maintenance methyltransferase xDNMT1 during Xenopus development results in premature transcription and activation of a p53-dependent apoptotic program that accounts for embryo lethality. Here, we show that activation of the apoptotic response is signalled through the methyl-CpG binding protein xMBD4 and the mismatch repair pathway protein xMLH1. Depletion of xMBD4 or xMLH1 increases the survival rate of xDNMT1-depleted embryos, whereas overexpression of these proteins in embryos induces programmed cell death at the onset of gastrulation. MBD4 interacts directly with both DNMT1 and MLH1, leading to recruitment of the latter to heterochromatic sites that are coincident with DNMT1 localisation. Time-lapse microscopy of micro-irradiated mammalian cells shows that MLH1/MBD4 (like DNMT1) can accumulate at DNA damage sites. We propose that xMBD4/xMLH1 participates in a novel G2 checkpoint that is responsive to xDNMT1p levels in developing embryos and cells.
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PMID:MBD4 and MLH1 are required for apoptotic induction in xDNMT1-depleted embryos. 1950 88

Early exposure to xenoestrogens may predispose to breast cancer risk later in adult life. It is likely that long-lived, self-regenerating epithelial progenitor cells are more susceptible to these exposure injuries over time and transmit the injured memory through epigenetic mechanisms to their differentiated progeny. Here, we used progenitor-containing mammospheres as an in vitro exposure model to study this epigenetic effect. Expression profiling identified that, relative to control cells, 9.1% of microRNAs (82 of 898 loci) were altered in epithelial progeny derived from mammospheres exposed to a synthetic estrogen, diethylstilbestrol. Repressive chromatin marks, trimethyl Lys27 of histone H3 (H3K27me3) and dimethyl Lys9 of histone H3 (H3K9me2), were found at a down-regulated locus, miR-9-3, in epithelial cells preexposed to diethylstilbestrol. This was accompanied by recruitment of DNA methyltransferase 1 that caused an aberrant increase in DNA methylation of its promoter CpG island in mammosphere-derived epithelial cells on diethylstilbestrol preexposure. Functional analyses suggest that miR-9-3 plays a role in the p53-related apoptotic pathway. Epigenetic silencing of this gene, therefore, reduces this cellular function and promotes the proliferation of breast cancer cells. Promoter hypermethylation of this microRNA may be a hallmark for early breast cancer development, and restoration of its expression by epigenetic and microRNA-based therapies is another viable option for future treatment of this disease.
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PMID:Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells. 1954 97

Expression of the p16(Ink4a) tumor suppressor gene, a sensor of oncogenic stress, is up-regulated by a variety of potentially oncogenic stimuli in cultured primary cells. However, because p16(Ink4a) expression is also induced by tissue culture stress, physiological mechanisms regulating p16(Ink4a) expression remain unclear. To eliminate any potential problems arising from tissue culture-imposed stress, we used bioluminescence imaging for noninvasive and real-time analysis of p16(Ink4a) expression under various physiological conditions in living mice. In this study, we show that oncogenic insults such as ras activation provoke epigenetic derepression of p16(Ink4a) expression through reduction of DNMT1 (DNA methyl transferase 1) levels as a DNA damage response in vivo. This pathway is accelerated in the absence of p53, indicating that p53 normally holds the p16(Ink4a) response in check. These results unveil a backup tumor suppressor role for p16(Ink4a) in the event of p53 inactivation, expanding our understanding of how p16(Ink4a) expression is regulated in vivo.
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PMID:Real-time in vivo imaging of p16Ink4a reveals cross talk with p53. 1966 29

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

The salvage anti-tumoral pathway which implicates the p53-related p73 gene is not yet fully characterized. We therefore attempted to identify the up- and down-stream events involved in the activation of the p73-dependent pro-apoptotic pathway, by focusing on the anti-apoptotic and epigenetic integrator UHRF1 which is essential for cell cycle progression. For this purpose, we analyzed the effects of a known anti-neoplastic drug, thymoquinone (TQ), on the p53-deficient acute lymphoblastic leukemia (ALL) Jurkat cell line. Our results showed that TQ inhibits the proliferation of Jurkat cells and induces G1 cell cycle arrest in a dose-dependent manner. Moreover, TQ treatment triggers programmed cell death, production of reactive oxygen species (ROS) and alteration of the mitochondrial membrane potential (DeltaPsim). TQ-induced apoptosis, confirmed by the presence of hypodiploid G0/G1 cells, is associated with a rapid and sharp re-expression of p73 and dose-dependent changes of the levels of caspase-3 cleaved subunits. These modifications are accompanied by a dramatic down-regulation of UHRF1 and two of its main partners, namely DNMT1 and HDAC1, which are all involved in the epigenetic code regulation. Knockdown of p73 expression restores UHRF1 expression, reactivates cell cycle progression and inhibits TQ-induced apoptosis. Altogether our results showed that TQ mediates its growth inhibitory effects on ALL p53-mutated cells via the activation of a p73-dependent mitochondrial and cell cycle checkpoint signaling pathway which subsequently targets UHRF1.
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PMID:Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1. 2002 9

Chronic stress is associated with more rapid tumor progression, and recent evidence suggests that stress may contribute to social and ethnic disparities in the incidence and mortality of breast cancer. We evaluated the p53(+/-) FVB/N mouse as a model to investigate effects of chronic social stress on mammary gland development, gene expression, and tumorigenesis. We individually housed (IH) wild-type and p53(+/-) female FVB/N mice, starting at weaning. At 14 weeks of age, both wild-type and p53(+/-) IH mice showed strikingly reduced mammary development compared with group-housed (GH) controls, with IH mice having significantly fewer preterminal end buds. This morphologic difference was not reflected in levels of mammary transcripts for estrogen receptor-alpha or progestin receptor. However, IH increased levels of mRNA for the kisspeptin receptor in the medial preoptic area of the hypothalamus, associated with reduced duration of estrous cycles. Furthermore, IH altered mammary transcripts of genes associated with DNA methylation; transcripts for methyl-binding protein 2 and DNA methyltransferase 3b (DNMT3b), but not DNMT1 and DNMT3a, were reduced in IH compared with GH females. Interestingly, the glands of p53(+/-) females showed reduced expression of all these mediators compared with wild-type females. However, contrary to our initial hypothesis, IH did not increase mammary tumorigenesis. Rather, p53(+/-) GH females developed significantly more mammary tumors than IH mice. Together, these data suggest that social isolation initiated at puberty might confound studies of tumorigenesis by altering mammary development in mouse models.
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PMID:Social isolation reduces mammary development, tumor incidence, and expression of epigenetic regulators in wild-type and p53-heterozygotic mice. 2042 36

The role of the cancer/testis antigen CAGE in drug resistance was investigated. The drug-resistant human melanoma Malme3M (Malme3M(R)) and the human hepatic cancer cell line SNU387 (SNU387(R)) showed in vivo drug resistance and CAGE induction. Induction of CAGE resulted from decreased expression and thereby displacement of DNA methyltransferase 1(DNMT1) from CAGE promoter sequences. Various drugs induce expression of CAGE by decreasing expression of DNMT1, and hypomethylation of CAGE was correlated with the increased expression of CAGE. Down-regulation of CAGE in these cell lines decreased invasion and enhanced drug sensitivity resulting from increased apoptosis. Down-regulation of CAGE also led to decreased anchorage-independent growth. Down-regulation of CAGE led to increased expression of p53, suggesting that CAGE may act as a negative regulator of p53. Down-regulation of p53 enhanced resistance to drugs and prevented drugs from exerting apoptotic effects. In SNU387(R) cells, CAGE induced the interaction between histone deacetylase 2 (HDAC2) and Snail, which exerted a negative effect on p53 expression. Chromatin immunoprecipitation assay showed that CAGE, through interaction with HDAC2, exerted a negative effect on p53 expression in Malme3M(R) cells. These results suggest that CAGE confers drug resistance by regulating expression of p53 through HDAC2. Taken together, these results show the potential value of CAGE as a target for the development of cancer therapeutics.
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PMID:Cancer/testis antigen CAGE exerts negative regulation on p53 expression through HDAC2 and confers resistance to anti-cancer drugs. 2053 91

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

Given the poor outcome of patients with hormone-resistant (HR) prostate cancer, new strategies are needed to improve the current therapeutic regimens and/or develop novel treatments. We therefore aimed to provide a better understanding of the molecular mechanisms involved in the aggressive tumor behavior of HR and develop more rational anti-tumor therapies. Three HR prostate cancer cell lines (androgen receptor (AR)-positive LNCaP-HR and 22RV1-HR and AR-negative PC-3) were used. Changes in tumor behavior, treatment response, and related signaling in HR were investigated in vitro and in vivo. The results revealed that constitutional activation of STAT3 and overexpressions of DNMT1 were important in the transition of HR prostate cancer. Furthermore, DNMT1 expression was required for the maintenance of STAT3 activation. When DNMT1 activity in HR was blocked, aggressive tumor behavior and treatment resistance could be overcome, which was seen in both in vitro and in vivo experiments. The underlying changes associated with inhibited DNMT1 included less epithelial-mesenchymal changes, less invasion ability, slower tumor growth, and impaired DNA repair ability, which are independent of AR and p53 status. In conclusion, altered DNMT1 expression associated with activated STAT3 may be crucial in the transition of HR. Targeting DNMT1 could be a promising strategy for the treatment of HR prostate, as evidenced by inhibited tumor growth and enhanced radiosensitivity. These findings provide evidence for therapeutically targeting DNMT1 in HR prostate cancer.
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PMID:Role of DNA methyltransferase 1 in hormone-resistant prostate cancer. 2054 41

Lysine-specific demethylase 1 (LSD1/KDM1) demethylates histone H3, in addition to tumor suppressor p53 and DNA methyltransferase 1 (Dnmt1), thus regulating eukaryotic gene expression by altering chromatin structure. Specific inhibitors of LSD1 are desired as anticancer agents, because LSD1 aberrations are associated with several cancers, and LSD1 inhibition restores the expression of abnormally silenced genes in cancerous cells. In this study, we designed and synthesized several candidate compounds to inhibit LSD1, based on the structures of LSD1 and monoamine oxidase B (MAO-B), in complex with an antidepressant tranylcypromine (2-PCPA) derivative. Compound S2101 exhibited stronger LSD1 inhibition than tranylcypromine and the known small LSD1 inhibitors in LSD1 demethylation assays, with a k(inact)/K(I) value of 4560 M(-1) s(-1). In comparison with tranylcypromine, the compound displayed weaker inhibition to the monoamine oxidases. The inhibition modes of the two 2-PCPA derivatives, 2-PFPA and S1201, were identified by determination of the inhibitor-bound LSD1 structures, which revealed the enhanced stability of the inhibitor-FAD adducts by their interactions with the surrounding LSD1 residues. These molecules are potential pharmaceutical candidates for cancer or latent virus infection, as well as research tools for LSD1-related biological investigations.
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PMID:Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1 . 2056 32


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