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)

Small DNA viruses are dependent on the interaction of early proteins (such as large T antigen) with host p53 and Rb to bring about the G1-to-S cell cycle transition. The large DNA viruses are less dependent on host regulatory genes since additional early viral proteins (such as viral DNA polymerase, DNA metabolic enzymes, and other replication proteins) are involved in DNA synthesis. A highly conserved domain of large T antigen (similar to the p53-binding region) exclusively identifies papovavirus, parvovirus, and papillomaviruses from all other larger DNA viruses and implies a conserved interaction with host regulatory genes. In this report, we show that 3 to 6 mM butyrate, a general cell cycle blocker implicated in inhibition of the G1-to-S transition, inhibits DNA replication of polyomavirus and human papillomavirus type 11 but not the replication of larger DNA viruses such as adenovirus types 2 and 5, herpes simplex virus type 1, Epstein-Barr virus, and cytomegalovirus, which all bypass the butyrate-mediated cell cycle block. This butyrate effect on polyomavirus replication is not cell type specific, nor does it depend on the p53 or Rb gene, as inhibition was seen in fibroblasts with intact or homozygous deleted p53 or Rb, 3T6 cells, keratinocytes, C2C12 myoblasts, and 3T3-L1 adipocytes. In addition, butyrate did not inhibit expression of polyomavirus T antigen. The antiviral effect of butyrate involves a form of imprinted state, since pretreatment of cells with 3 mM butyrate inhibits human papillomavirus type 11 DNA replication for at least 96 h after its removal. Butyrate, therefore, serves as a molecular tool in dissecting the life cycle of smaller DNA viruses from that of the larger DNA viruses in relation to the cell cycle.
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PMID:n-Butyrate, a cell cycle blocker, inhibits the replication of polyomaviruses and papillomaviruses but not that of adenoviruses and herpesviruses. 803 79

Butyric acid is a potent cell growth inhibitor and differentiation inducer. Our previous studies have shown that MAG=3but, a monosaccharide ester of butyric acid, used at 1 mM, induces apoptosis in the HL-60 cell line. We report here that this drug can also induce apoptosis in the U-937 leukemic cell lines whereas the myeloblastic KG1 and the NB4 promyelocytic leukemic cell lines were refractory to induction of apoptosis. In order to determine what can trigger cells to undergo apoptosis, cell cycle analysis, induction of differentiation and p53, c-myc and Bcl-2 expression was studied. Apoptosis was correlated to an arrest of cell growth in the G1 phase of the cell cycle and to an induction of differentiation through the monocytic pathway in HL-60 and U-937 cells. Time course studies demonstrated DNA fragmentation after few hours incubation with the drug, while morphological signs appeared later (days 2 or 3). Northern blot analysis and flow cytometric studies have shown that cell death induced by MAG=3but was not associated to an overexpression of c-myc and p53. However, in the HL-60 cells, BCL-2 protein expression was decreased after MAG=3but treatment, corroborating the apoptosis observed.
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PMID:Selective induction of apoptosis in myeloid leukemic cell lines by monoacetone glucose-3 butyrate. 819 84

Butyrate is a well known colonic luminal short chain fatty acid, which arrests cell growth and induces differentiation in various cell types. We examined the effect of butyrate on the expression of WAF1/Cip1, a potent inhibitor of cyclin-dependent kinases, and its relation to growth arrest in a p53-mutated human colon cancer cell line WiDr. Five millimolar butyrate completely inhibited the growth of WiDr and caused G1-phase arrest. WAF1/Cip1 mRNA was rapidly induced within 3 h by treatment with 5.0 mM butyrate, and drastic WAF1/Cip1 protein induction was detected. Using several mutant WAF1/Cip1 promoter fragments, we found that the butyrate-responsive elements are two Sp1 sites at -82 and -69 relative to the transcription start site. We also found that a TATA element at -46 and two overlapping consensus Sp1 sites at -60 and -55 are essential for the basal promoter activity of WAF1/Cip1. These findings suggest that butyrate arrests the growth of WiDr by activating the WAF1/Cip1 promoter through specific Sp1 sites in a p53-independent fashion.
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PMID:Butyrate activates the WAF1/Cip1 gene promoter through Sp1 sites in a p53-negative human colon cancer cell line. 926 65

Butyrate, a physiologically occurring agent, has been reported to decrease constitutively high expressed p53 levels in transformed cells. To elucidate whether butyrate also inhibits DNA-damage-induced p53 response we investigated the effects of butyrate and the anticancer drug mitomycin C in normal C3H10T1/2 cells harbouring wild-type p53. In comparison with p53-deficient fibroblasts we examined p53 protein level, cell cycle arrest, differentiation, and apoptosis. Butyrate induced G1 phase arrest, differentiation, and p53-independent increase in p21(waf1/cip1) protein. Moreover, butyrate induced p53-independent apoptosis, which was, as well as p53-mediated apoptosis, associated with a dose-dependent increase in Bax and c-Myc protein. Pretreatment with butyrate repressed dose-dependently mitomycin-C-induced p53 accumulation and interfered with p53-dependent cell cycle arrest. Butyrate further partially inhibited p53-mediated apoptosis, but low doses of butyrate were more effective than higher concentrations. This was reflected in an enhanced decrease in c-Myc and Bax protein in response to mitomycin C with low concentrations of butyrate. Our data indicate that the differentiation stimulus of butyrate, in association with p21(waf1/cip1) induction, and apoptosis, may explain antineoplastic effects of butyrate. Co-carcinogenic features of butyrate may result from inhibition of p53-mediated DNA damage response.
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PMID:Butyrate modulates DNA-damage-induced p53 response by induction of p53-independent differentiation and apoptosis. 933 15

A diet high in fiber is associated with a decreased incidence and growth of colon cancers. Butyrate, a four-carbon short-chain fatty acid product of fiber fermentation within the colon, appears to mediate these salutary effects. We sought to determine the molecular mechanism by which butyrate mediates growth inhibition of colonic cancer cells and thereby to elucidate the molecular link between a high-fiber diet and the arrest of colon carcinogenesis. We show that concomitant with growth arrest, butyrate induces p21 mRNA expression in an immediate-early fashion, through transactivation of a promoter cis-element(s) located within 1.4 kb of the transcriptional start site, independent of p53 binding. Studies using the specific histone hyperacetylating agent, trichostatin A, and histone deacetylase 1 indicate that growth arrest and p21 induction occur through a mechanism involving histone hyperacetylation. We show the critical importance of p21 in butyrate-mediated growth arrest by first confirming that stable overexpression of the p21 gene is able to cause growth arrest in the human colon carcinoma cell line, HT-29. Furthermore, using p21-deleted HCT116 human colon carcinoma cells, we provide convincing evidence that p21 is required for growth arrest to occur in response to histone hyperacetylation, but not for serum starvation nor postconfluent growth. Thus, p21 appears to be a critical effector of butyrate-induced growth arrest in colonic cancer cells, and may be an important molecular link between a high-fiber diet and the prevention of colon carcinogenesis.
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PMID:p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells. 961 91

The Cdc25 dual specificity phosphatase family has a central role in controlling cell cycle progression and has been implicated in the etiology of cancer. One compound, 4-(benzyl-(2-[(2, 5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylami no butyric acid (SC-alpha alpha delta 9), was previously identified as the most potent reported synthetic inhibitor of Cdc25 phosphatases in vitro. In the present study, we demonstrate that SC-alpha alpha delta 9 inhibited Cdc25-dependent cell cycle progression at both G1 and G2/M phase using tsFT210 cells, which express a temperature-sensitive Cdc2 mutant. SC-alpha alpha delta 9 blocked both G2/M transition and dephosphorylation of Cdc2 in a concentration-dependent manner. SC-alpha alpha delta 9 also enhanced tyrosine phosphorylation of both Cdk2 and Cdk4, and decreased Cdk4 kinase activity. Both of the kinases are potent regulators of G1 transition. Furthermore, closely related chemical analogs that lacked Cdc25 inhibitory activity failed to block cell cycle progression at both G1 and G2/M, and did not affect Cdc2 phosphorylation or Cdk4 kinase activity. SC-alpha alpha delta 9 did not alter p53, p21 or p16 levels. Our results support the hypothesis that the disruption in cell cycle transition caused by SC-alpha alpha delta 9 was due to intracellular Cdc25 inhibition. We propose that the SC-alpha alpha delta 9 pharmacophore could be useful in further clarifying the role of Cdc25 phosphatase-dependent pathways in checkpoint control, oncogenesis, and apoptosis.
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PMID:Dual G1 and G2/M phase inhibition by SC-alpha alpha delta 9, a combinatorially derived Cdc25 phosphatase inhibitor. 1059 98

The cyclin-dependent kinase inhibitor p21/WAF1/CIP1 is induced in many cell types in response to a variety of extracellular signals and causes cell cycle arrest in both the G1 and G2/M phases of the cell cycle. We reported previously that calcitonin (CT) receptor (CTR)-mediated growth inhibition of HEK-293 cells stably transfected with the human CTR is accompanied by a rapid and sustained induction of p21 and cell cycle arrest in G2. In the present study we have shown that CT stimulates transcription from a p21 promoter-luciferase construct. Using deletion and mutation analysis of the p21 promoter we have demonstrated that transcriptional activation of p21 by CT is p53-independent and is mediated through specific activation of Sp1-binding sites in a region of the promoter between -82 and -69, relative to the transcription start site. CTR-mediated transcriptional activation of p21 was specific for the insert-negative isoform of the human CTR. Butyrate, which was shown previously to activate the same Sp1 site, synergised with CT to increase further p21 promoter activity. These results provide the first demonstration that CTR can induce gene transcription through the constitutively expressed transcription factor Sp1, and define a mechanism of cell growth suppression that may have implications for other members of the seven-transmembrane domain G protein-coupled receptor superfamily.
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PMID:Identification of a novel calcitonin-response element in the promoter of the human p21WAF1/CIP1 gene. 1101 46

Butyric acid, an extracellular metabolite from periodontopathic bacteria, induces apoptosis in murine thymocytes, splenic T-cells, and human Jurkat T-cells. The present study examines the contributions of apoptosis-related proteins (Bcl-2, Bcl-XL, Bax, and p21WAF1/CIP1) in the regulation of T-cell death induced by butyric acid, using p53 knock-out (p53-/-) and wild-type (p53+/+) mice. The results of a DNA fragmentation assay indicated that thymocytes, splenic T-cells, and B-cells from p53-/- mice were susceptible to butyric-acid-induced apoptosis to a degree similar to those from p53+/+ mice. Moreover, butyric acid significantly induced apoptosis in lymphocytes from both p53+/+ and p53-/- mice in a concentration- and time-dependent fashion. Experiments with fractionated subpopulations of splenic T-cells revealed that DNA fragmentation was equally observed in CD4+ and CD8+ splenic T-cells from both p53+/+ and p53-/- lymphocytes. Activation of caspase-3, caspase-6, and caspase-8, but not of caspase-1, in butyric-acid-induced T-cell apoptosis occurred regardless of the presence of p53. Western blotting analysis of splenic T-cells showed that butyric acid treatment decreased Bcl-2 and Bcl-XL expressions in p53+/+ and p53-/- cells. Splenic T-cells had barely detectable Bax and p21WAF1/CIP1, regardless of whether butyric acid and/or p53 was present. These results suggest that butyric-acid-mediated apoptosis of murine T-cells takes place via a pathway that is independent of p53, and is followed by the p53-regulated proteins Bax and p21WAF1/CIP1, which lower the levels of the apoptosis antagonists Bcl-2 and Bcl-XL in cells.
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PMID:Butyric-acid-induced apoptosis in murine thymocytes and splenic T- and B-cells occurs in the absence of p53. 1120 Oct 44

1. This study was performed to determine the effect and action mechanisms of sodium butyrate (NaB) on the growth of breast cancer cells. 2. Butyrate inhibited the growth of all breast cancer cell lines analysed. It induced cell cycle arrest in G1 and apoptosis in MCF-7, MCF-7ras, T47-D, and BT-20 cells, as well as arrest in G2/M in MDA-MB-231 cells. 3. Transient transfection of MCF-7 and T47-D cells with wild-type and antisense p53 did not modify butyrate-induced apoptosis. Pifithrin-alpha, which inhibits the transcriptional activity of P53, did not modify cell growth or apoptosis of MCF-7 and T47-D cells treated with butyrate. These results indicate that P53 was not involved in butyrate-induced growth inhibition of breast cancer cells. 4. Treatment of MCF-7 cells with anti-Fas agonist antibody induced cell death, indicating that Fas was functional in these cells. Moreover, butyrate potentiated Fas-induced apoptosis, as massive apoptosis was observed rapidly when MCF-7 cells were treated with butyrate and anti-Fas agonist antibody. In addition, butyrate-induced apoptosis in MCF-7 cells was considerably reduced by anti-Fas antagonist antibody. Western blot analysis showed that butyrate increased Fas and Fas ligand levels (Fas L), indicating that butyrate-induced apoptosis may be mediated by Fas signalling. 5. These results demonstrate that butyrate inhibited the growth of breast cancer cells in a P53-independent manner. Moreover, it induced apoptosis via the Fas/Fas L system and potentiated Fas-triggered apoptosis in MCF-7 cells. These findings may open interesting perspectives in human breast cancer treatment strategy.
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PMID:Sodium butyrate induces P53-independent, Fas-mediated apoptosis in MCF-7 human breast cancer cells. 1178 82

Lovastatin, the drug used for the treatment of hypercholesterolemia, has previously been reported to exert antitumor activity in experimental murine models. Butyrate and butyric acid derivatives are well known to induce differentiation and apoptosis of tumour cells and also have recently gained acceptance as potential anticancer agents. In this study, we examined the antitumor effects of the combination of lovastatin and butyrate or its prodrug tributyrin in vitro and in vivo against a murine Lewis lung carcinoma (3LL). This combination therapy showed synergistic antitumor activity against 3LL cells in vitro. These effects were at least in part due to apoptosis induction that occurred after 12 hr of incubation with lovastatin and butyrate and was preceded by changes in cell cycle distribution of treated cells and expression of p21, p53 and cyclin D1. Remarkably, a systemic treatment of syngeneic mice inoculated with 3LL cells with both drugs resulted in significant tumour growth retardation.
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PMID:Potentiating antitumor effects of a combination therapy with lovastatin and butyrate in the Lewis lung carcinoma model in mice. 1185 49


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