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)

Tumor suppressor p53 is a transcription activator that upregulates target genes containing the p53 binding site. UREB1, a DNA binding protein that is tyrosine phosphorylated in vivo, shares a significant homology with the human papilloma virus E6 associated protein (E6-AP). E6-AP forms a ternary complex with E6 and p53 and participates in the ubiquitination of p53. Based on the homology with E6-AP, but taking into account the nuclear localization of UREB1 and its smaller size, the present study used a transient transfection system to examine whether UREB1 influenced p53-stimulated transcription. Co-transfection of a vector expressing wildtype UREB1 with one expressing p53 into H1299, a p53 negative cell line, resulted in a pronounced suppression of p53 transactivation. The inhibitory effect was significantly attenuated by mutation of a tyrosine residue in the consensus tyrosine phosphorylation sequence of UREB1. These data suggest that optimal suppression of p53 transactivation requires tyrosine phosphorylated UREB1 and that tyrosine phosphorylation and dephosphorylation processes may be involved in the regulation of p53 transactivation.
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PMID:UREB1, a tyrosine phosphorylated nuclear protein, inhibits p53 transactivation. 747 39

The retinoblastoma susceptibility gene (Rb) participates in controlling the G1/S-phase transition, presumably by binding and inactivating E2F transcription activator family members. Mouse embryonic fibroblasts (MEFs) with no, one, or two inactivated Rb genes were used to determine the specific contributions of Rb protein to cell cycle progression and gene expression. MEFs lacking both Rb alleles (Rb-/-) entered S phase in the presence of the dihydrofolate reductase inhibitor methotrexate. Two E2F target genes, dihydrofolate reductase and thymidylate synthase, displayed elevated mRNA and protein levels in Rb- MEFs. Since absence of functional Rb protein in MEFs is sufficient for S-phase entry under growth-limiting conditions, these data indicate that the E2F complexes containing Rb protein, and not the Rb-related proteins p107 and p130, may be rate limiting for the G1/S transition. Antineoplastic drugs caused accumulation of p53 in the nuclei of both Rb+/+ and Rb-/- MEFs. While p53 induction led to apoptosis in Rb-/- MEFs, Rb+/- and Rb+/+ MEFs underwent cell cycle arrest without apoptosis. These results reveal that diverse growth signals work through Rb to regulate entry into S phase, and they indicate that absence of Rb protein produces a constitutive DNA replication signal capable of activating a p53-associated apoptotic response.
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PMID:Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. 777 26

The p53 tumor suppressor gene product is a sequence-specific transcription activator frequently mutated in a variety of human malignancies. Typically, tumor-derived p53 missense mutants are defective in DNA binding and this is likely to result in a failure to active p53-regulated genes. Hence, restoring function to mutant p53 represents an attractive target to develop a novel cancer chemotherapeutic agent. We now show that a small chemically modified peptide derived from p53 restores sequence-specific DNA binding to a subset of p53 mutants. Moreover, when microinjected into human colon carcinoma cells this peptide restores the transcription activation function to endogenous mutant p53 protein. This is the first example showing that a small peptide molecule can reverse the effect of several inactivating missense mutations and restore protein function.
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PMID:Restoration of the transcription activation function to mutant p53 in human cancer cells. 895 91

p300 and the closely related CREB binding protein (CBP) are transcriptional adaptors that are present in intracellular complexes with TATA binding protein (TBP) and bind to upstream activators including p53 and nuclear hormone receptors. They have intrinsic and associated histone acetyltransferase activity, suggesting that chromatin modification is an essential part of their role in regulating transcription. Detailed characterization of a panel of antibodies raised against p300/CBP has revealed the existence of a 270-kDa cellular protein, p270, distinct from p300 and CBP but sharing at least two independent epitopes with p300. The subset of p300/CBP-derived antibodies that cross-reacts with p270 consistently coprecipitates a series a cellular proteins with relative molecular masses ranging from 44 to 190 kDa. Purification and analysis of various proteins in this group reveals that they are components of the human SWI/SNF complex and that p270 is an integral member of this complex.
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PMID:p300/CREB binding protein-related protein p270 is a component of mammalian SWI/SNF complexes. 958

Multidrug resistance is a major obstacle to the success of cancer chemotherapy. The multidrug resistance-associated protein (MRP) has been shown to confer multidrug resistance. To study MRP gene expression at the transcriptional level, we have fused the MRP gene promoter with the luciferase reporter gene and studied its regulation. Cotransfection of MRP promoter constructs with p53 expression plasmids in p53-null human H1299 and mouse (10)1 cells demonstrated that the wild-type (wt) p53 markedly suppressed MRP promoter activity, whereas mutant p53 had little inhibitory effect. Transfections using 5' deletion mutant constructs of the MRP promoter showed that inhibition of the promoter activity by wt p53 mainly resided in the region from -91 to +103 bp, where several Sp1 transcription factor binding sites are localized. Cotransfection of the MRP promoter into Drosophila SL2 cells with an Sp1 expression vector increased the promoter activity in a dose-related manner up to approximately 200-fold. The stimulation of MRP promoter activity by Sp1 was attenuated by the cotransfection of a wt p53-expression plasmid. Furthermore, we have determined that endogenous MRP mRNA levels were down-regulated by restoration of wt p53-expression in a human lung cancer cell line. The relevance of MRP regulation in drug resistance was studied in a drug-resistant cell line, CEM/VM-1-5, that is approximately 140-fold more resistant to the epipodophyllotoxin, teniposide (VM-26), than the parental CEM cells. CEM/VM-1-5 cells express a much higher amount of MRP mRNA and protein than CEM cells, indicating that the resistant phenotype is at least partly due to increased MRP production. Transient transfection of the promoter constructs revealed that CEM/VM-1-5 cells had higher (7-fold) MRP promoter activity than CEM cells. Cotransfection of a wt p53-expression plasmid caused a reduction of MRP promoter activity in both CEM and CEM/VM-1-5 cells, but the inhibition was more than double in CEM/VM-1-5 cells compared with CEM cells. Our results demonstrated that wt p53 acts as a negative regulator of MRP gene transcription, at least in part by diminishing the effect of a powerful transcription activator Sp1. Therefore, a loss of wt p53 function and/or an increase in Sp1 activity in tumor cells could contribute to an up-regulation of the MRP gene.
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PMID:Transcriptional suppression of multidrug resistance-associated protein (MRP) gene expression by wild-type p53. 986 34

The rat p53 promoter has several potential transcription factor-recognition motifs. They include NF1-like, bHLH family, and AP1-like proteins binding sites. The binding protein to NF1-like motif was previously identified. The protein has about 40kDa of molecular mass, which is smaller than that of NF1. Anti-NF1 polyclonal antibody does not recognize the protein. In this study, we isolated the 40kDa protein by sequence-specific DNA affinity chromatography. The isolated protein was assayed by DNase I footprinting analysis. To determine the transactivation effect of the protein, in vitro transcription with the purified 40kDa protein was carried out. After the addition of the purified 40kDa protein into the transcription reaction mixture, the transcription level of the p53 promoter was increased. This suggests that the 40 kDa NF1-like protein is a transcription activator for the rat p53 gene.
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PMID:In vitro transcription assay with the purified 40kDa NF1-like protein binding to the rat p53 promoter. 1020 79

Germline mutations in the tumor suppressor gene, BRCA1, predispose individuals to breast and ovarian cancers. Using a combination of affinity- and conventional chromatographic techniques, we have isolated a predominant form of a multiprotein BRCA1-containing complex from human cells displaying chromatin-remodeling activity. Mass spectrometric sequencing of components of this complex indicated that BRCA1 is associated with a SWI/SNF-related complex. We show that BRCA1 can directly interact with the BRG1 subunit of the SWI/SNF complex. Moreover, p53-mediated stimulation of transcription by BRCA1 was completely abrogated by either a dominant-negative mutant of BRG1 or the cancer-causing deletion in exon 11 of BRCA1. These findings reveal a direct function for BRCA1 in transcriptional control through modulation of chromatin structure.
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PMID:BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. 1094 45

Infection of HeLa cells with poliovirus leads to rapid shut-off of host cell transcription by RNA polymerase II. Previous results have suggested that both the basal transcription factor TBP (TATA-binding protein) and transcription activator proteins such as CREB (cyclic AMP-responsive element-binding protein) and Oct-1 (the octamer-binding factor) are cleaved by the viral-encoded protease, 3C(Pro). Here we demonstrate that the transcriptional activator (and tumor suppressor) p53 is degraded by the viral protease 3C both in vivo and in vitro. Unlike other transcription factors that are directly cleaved by 3C(pro), degradation of p53 requires a HeLa cell activity in addition to 3C(Pro). The degradation of p53 by 3C(Pro) does not appear to involve the ubiquitin pathway of protein degradation. Vaccinia virus infection of HeLa cells leads to inactivation of the cellular activity required for 3C(Pro)-mediated degradation of p53. The vaccinia-encoded protein (CrmA) is known to inhibit caspase I (ICE protease) that converts inactive IL-1beta to an active secreted form. Incubation of HeLa cells with caspase I inhibitor Z-VAD-fmk does not interfere with 3C(Pro)-mediated degradation of p53. The cellular activity present in extracts of HeLa cells can be fractionated through phosphocellulose. A partially purified fraction that elutes at 0.6 M KCl from phosphocellulose contains the activity that degrades p53 in a 3C(Pro)-dependent manner. These results suggest that both poliovirus-encoded protease 3C(Pro) and a cellular activity are required for the degradation of p53 observed in cells infected with poliovirus.
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PMID:Poliovirus 3C protease-mediated degradation of transcriptional activator p53 requires a cellular activity. 1187 95

The SWI/SNF complex is required for the transcription of several genes and has been shown to alter nucleosome structure in an ATP-dependent manner. The tumor suppressor protein p53 displays growth and transformation suppression functions that are frequently lost in mutant p53 proteins detected in various cancers. Using genetic and biochemical approaches, we show that several subunits of the human SWI/SNF complex bind to the tumor suppressor protein p53 in vivo and in vitro. The transactivation function of p53 is stimulated by overexpression of hSNF5 and BRG-1 and dominant forms of hSNF5 and BRG-1 repress p53-dependent transcription. Chromatin immunoprecipitation assay shows that hSNF5 and BRG-1 are recruited to a p53-dependent promoter in vivo. Overexpression of dominant negative forms of either hSNF5 or BRG-1 inhibited p53-mediated cell growth suppression and apoptosis. Molecular connection between p53 and the SWI/SNF complex implicates that (i) the SWI/SNF complex is necessary for p53-driven transcriptional activation, and (ii) the SWI/SNF complex plays an important role in p53-mediated cell cycle control.
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PMID:SWI/SNF complex interacts with tumor suppressor p53 and is necessary for the activation of p53-mediated transcription. 1195 Aug 34

A role for the SWI/SNF complex in tumorigenesis based on its requirement for retinoblastoma induced growth arrest and p53-mediated transcription and the appearance of tumors in SWI/SNF-deficient mice. In addition, Western blot data have shown that the SWI/SNF ATPase subunits cell, BRG1 and BRM (BRG1/BRM), are lost in approximately 30% of human non-small lung cancer cell lines. To determine whether loss of expression of these proteins occurs in primary tumors, we examined their expression in 41 primary lung adenocarcinomas and 19 primary lung squamous carcinomas by immunohistochemistry. These analyses showed that 10% of tumors show a concomitant loss of BRG1 and BRM expression. Moreover, patients with BRG1/BRM-negative carcinomas, independent of stage, have a statistically significant decrease in survival compared with patients with BRG1/BRM. This report provides supportive evidence that BRG1 and BRM act as tumor suppressor proteins and implicates a role for their loss in the development of non-small cell lung cancers.
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PMID:Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. 1256 96


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