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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53 is an extensively studied tumor suppressor gene implicated in the genesis of a large number of varied tumors. However, the pathways of regulation for the wild-type p53 gene and its product are as yet unknown. In situ hybridization analyses of ETS1 and ETS2 expression during mouse embryogenesis, have shown a pattern similar to that of p53 gene expression. Significantly, we have identified several ETS-binding sites (EBS) in the promoter regions of the human and mouse p53 genes. In the human promoter two of these EBS are present in the form of a palindrome, with the two EBS cores being separated by four nucleotides. This report shows that the EBS palindrome of the human p53 promoter has a high affinity for ETS1 and ETS2 and that such binding interaction intracellularly is able to activate the transcription of a CAT reporter gene by 5-10-fold using COS cells. To investigate whether the spacing between the two EBS cores influences the DNA binding activity, we synthesized oligonucleotides with increasing distances (4,12,16, and 20 bases respectively) between the two EBS cores of the palindrome. We observed an inverse correlation between an increasing distance in the two EBS cores of the palindrome and the ETS1 and ETS2 DNA binding activity respectively. Interestingly, optimal DNA binding activity was observed when the distance between the two EBS cores was four bases, identical to that which occurs in the natural promoter. Furthermore we show that the p53 mRNA is expressed at higher levels in NIH3T3 cells overexpressing ETS2 gene product, suggesting that the ETS2 transcription factor is a likely candidate for regulating the expression of p53 in vivo.
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PMID:ETS1 and ETS2 in p53 regulation: spatial separation of ETS binding sites (EBS) modulate protein: DNA interaction. 864 21

Cyclin-dependent protein kinases (Cdks) play a key role in the cell division cycle of eukaryotic cells. Cdc2, the first mammalian Cdk that was discovered, is expressed in S phase and functions in the G2 to M phase transition. By transfecting segments of the human cdc2 promoter linked to a reporter gene into monkey kidney (CV-1) cells, we identified the region containing the Sp1, E2F, and two CCAAT box binding sites as essential and sufficient for basal transcription. SV40 large T antigen (SV40-LT) is a viral oncoprotein that transactivates viral and cellular promoters and induces DNA synthesis in quiescent cells. SV40-LT transactivated wild-type cdc2 promoter/reporter constructs in a dose-dependent manner, coinciding with an increase in endogenous cdc2 mRNA. A mutant promoter from which the two CCAAT box motifs were deleted was 8-fold less sensitive to SV40-LT. Activation by SV40-LT did not require its ability to bind the retinoblastoma or p53 tumor suppressor proteins. SV40-LT induced a specific CCAAT box-binding factor (CBF) in CV-1 and COS-7 cells, as judged by gel shift and Southwestern analyses. Similar results were obtained in human fibroblasts expressing a conditional SV40-LT. The SV40-LT-inducible CBF appears to be novel and differs from the CBF that activates heat shock protein 70 gene expression.
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PMID:SV40 large T antigen transactivates the human cdc2 promoter by inducing a CCAAT box binding factor. 866 14

The p53 tumour suppressor protein is thought to play a major role in the defence of the cell against agents which damage DNA. p53 is phosphorylated at multiple sites in vivo and by several different protein kinases in vitro. In this report, we have examined the phosphorylation of murine p53 by protein kinase C (PKC). Phosphopeptide mapping, phosphoamino acid analysis and radiosequence analysis of p53 phosphorylated by PKC in vitro indicated that serine 370 and threonine 377 were the major targets for phosphorylation and suggested that serine 372 and threonines 365 and 371 were minor phosphorylation sites. Site-directed mutagenesis confirmed that residues 370-372, all of which lie within the epitope for monoclonal antibody PAb421, were phosphorylated in vitro. The p53 from 32P-labelled SV3T3 cells showed a phosphopeptide pattern which includes peptides with mobilities similar to those arising from phosphorylation of residues 370-372 by PKC in vitro. Only two of these in vivo-labelled phosphopeptides co-migrated in two dimensions with peptides labelled in vitro within the PAb421 epitope and their phosphorylation was not stimulated by the addition of the PKC activator o-tetradecanoylphorbol 13-acetate (TPA) to the cells, even though this treatment led to a fourfold stimulation of p53 phosphorylation by MAP kinase. Moreover, when the p53 proteins containing mutations at residues 370-372 were expressed in COS cells, there was no loss of any of the in vivo phosphopeptides, indicating that phosphorylation within the PAb42I epitope was undetectable in the cell. These data suggest that p53 and PKC may not interact in vivo. The two-dimensional migration pattern of the novel group of peptides is consistent with phosphorylation of previously uncharacterised sites within the central DNA binding region of p53.
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PMID:Murine p53 is phosphorylated within the PAb421 epitope by protein kinase C in vitro, but not in vivo, even after stimulation with the phorbol ester o-tetradecanoylphorbol 13-acetate. 870 May 48

We describe the cloning and sequence analysis of a nearly full-length cDNA as well as a corresponding 5.2-kilobase pair genomic fragment encoding FREAC-4, a member of the forkhead family of transcription factors. The cDNA is collinear with respect to the coding region of the intronless genomic clone. The conceptual translation product predicts a protein of 465 amino acids with a hyperacidic amino-terminal end, a DNA binding forkhead domain and a carboxyl-terminal part that is rich in homopolymeric runs of prolines and alanines. The transcription start is identified using an RNase protection assay. A 2.7-kilobase pair genomic DNA fragment, located immediately upstream of the translation start, was fused to a luciferase reporter gene. Significant levels of luciferase activity were detected when this construct was transfected into two kidney-derived cell lines, 293 and COS-7 cells, whereas only background reporter gene expression was observed in a cell line of nonkidney origin. Cotransfections with plasmids expressing WT-1, WTAR (a mutated form of WT-1), p53, and a mutated form of p53 revealed a complex pattern of regulation with a 3-fold induction with WT-1, a 7-fold induction with mutated p53, and a 4-fold repression with wild-type p53. A 5'-promoter deletion series delimits a DNA fragment necessary for WT-1 inducibility in cotransfection experiments. This fragment is shown to contain at least one cis-element that is capable of interacting with recombinant WT-1.
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PMID:Characterization of the human forkhead gene FREAC-4. Evidence for regulation by Wilms' tumor suppressor gene (WT-1) and p53. 870 77

As p53 is transcriptionally inactive in COS-1 cells, we felt it would be interesting to study the relative time course of expression of nuclear p53 and the onset of S phase. Our results indicated that the expression of nuclear p53 lagged behind the onset of S phase in COS-1 cells. In addition, rapid nuclear expression of p53, probably resulting from nuclear translocation, occurred immediately after the addition of serum into COS1 cells. No such phenomena were found in B104-1 and BHK cells.
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PMID:Expression pattern of nuclear p53 is unique in COS-1 cells. 891 74

A gene encoding a single-chain antibody (scFv) which specifically binds the tumor suppressor protein p53 has been constructed from RNA of hybridoma cells producing Pab 421. scFv-421 which was expressed and purified from bacteria specifically binds p53. scFv-421, as well as the previously described scFv-FRP5 and -R1R (1), were expressed intracellularly in mammalian cells and targeted to different subcellular locations, including the nucleus, cytoplasm, and endoplasmic reticulum (ER). High levels of all ER targeted scFv proteins, but not nuclear or cytoplasmic targeted proteins, were found in transfected COS-1 cells. In an attempt to stabilize the proteins, sequences encoding the mouse immunoglobin CK constant domain were added to each scFv construct. This led to a moderate increase in the cytoplasmic expression of scFv-FRP5.
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PMID:Characterization of scFv-421, a single-chain antibody targeted to p53. 901 57

The Interleukin-1beta converting enzyme (ICE) family of proteins, homologs of the C elegans cell death gene product CED-3, play important roles in controlling vertebrate programmed cell death. Because inhibition of apoptosis may be an essential step in tumorigenesis, we investigated the interaction of the simian virus 40 large T antigen (T ag) with the ICE family. COS-1 cells which were transformed by the simian virus 40 do not die when transfected with expression constructs of Ice or Ich-1(L). We found that expression of T ag alone significantly prevents the ICE-induced apoptosis. p53, but not pRb or p107, antagonizes the effect of T ag on the suppression of ICE-induced cell death, but not on ICH-1(L)-mediated cell death. Thus, wild type p53 may potentiate ICE-induced apoptosis. Expression of a temperature sensitive mutant p53Val(135) sensitizes COS-1 cells to apoptosis induced by ICE at permissive but not at non-permissive temperature. While induction of bax, p21(WAF1/CIP), or cyclin D1 gene expression is observed in the COS-1 p53Val(135) cells at the permissive temperature, overexpression of bax, but not p21(WAF1/CIP) or cyclin D1, potentiates ICE-induced COS-1 cell death. Taken together, these results suggest that T ag may modulate the cells' susceptibility to death by suppressing activity of the ICE family through inhibiting p53.
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PMID:Suppression of interleukin-1beta converting enzyme (ICE)-induced apoptosis by SV40 large T antigen. 912 70

Necdin is a nuclear protein expressed in virtually all postmitotic neurons, and ectopic expression of this protein strongly suppresses the proliferation of NIH3T3 cells. Simian virus 40 large T antigen targets both p53 and the retinoblastoma protein (Rb) for cellular transformation. By analogy with the interactions of the large T antigen with these nuclear growth suppressors, we examined the ability of necdin to bind to the large T antigen. Necdin was co-immunoprecipitated with the large T antigen from the nuclear extract of necdin cDNA-transfected COS-1 cells. Yeast two-hybrid and in vitro binding analyses revealed that necdin bound to an amino-terminal region of the large T antigen, which encompasses the Rb-binding domain. Moreover, necdin bound to adenovirus E1A, another viral oncoprotein that forms a specific complex with Rb. We then examined the ability of necdin to bind to the transcription factor E2F1, a cellular Rb-binding factor involved in cell-cycle progression. Intriguingly, necdin, like Rb, bound to a carboxyl-terminal domain of E2F1, and repressed E2F-dependent transactivation in vivo. In addition, necdin suppressed the colony formation of Rb-deficient SAOS-2 osteosarcoma cells. These results suggest that necdin is a postmitotic neuron-specific growth suppressor that is functionally similar to Rb.
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PMID:Necdin, a postmitotic neuron-specific growth suppressor, interacts with viral transforming proteins and cellular transcription factor E2F1. 942 23

Brain-specific angiogenesis inhibitor 1 (BAI1), which is a p53-target gene specifically expressed in brain, encodes a seven-span transmembrane protein. Using a two-hybrid system, we isolated a cDNA that encodes a protein, named BAP1 (BAI1-associated protein), which interacts with the cytoplasmic region of BAI1. BAP1 is a novel member of the MAGUK (membrane-associated guanylate kinase homologue) family; it possesses a guanylate kinase domain, WW domains, and multiple PDZ domains. Interaction between BAI1 and BAP1 was mediated by a QTEV motif in the carboxy-terminal region of BAI1 and PDZ domains of BAP1. By immunocytochemical analysis of COS-7 cells transfected with BAI1 and BAP1, both products were co-localized at the cytoplasmic membrane, especially at cell-cell junctions. Cells transfected with BAI1 formed filopodia-like cytoplasmic extensions. These results suggest that BAI1 and BAP1 might be involved in cell adhesion and signal transduction in brain.
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PMID:Cloning and characterization of BAI-associated protein 1: a PDZ domain-containing protein that interacts with BAI1. 964 39

BAI1 (brain-specific angiogenesis inhibitor 1) was originally isolated as a p53-target gene specifically expressed in brain. To clarify its function, we have been searching for cellular proteins that associate with the cytoplasmic domain of BAI1. Using its intracellular carboxyl terminus as "bait" in a yeast two-hybrid system, we isolated a cDNA clone named BAIAP2 whose nucleotide sequence would encode a 521-amino acid protein showing significant homology to a 58/53-kDa substrate of insulin-receptor kinase in the hamster. As the expression profile of BAIAP2 examined by Northern blot analysis was almost identical to that of BAI1, BAIAP2 appears to be active mainly in neurons. In vitro binding assays confirmed that a proline-rich cytoplasmic fragment of BAI1 interacted with the Src homology 3 (SH3) domain of BAIAP2. Double-color immunofluorescent analysis revealed that BAIAP2 was localized at the cytoplasmic membrane when it was coexpressed with BAI1 in COS-7 cells; BAIAP2 not associated with BAI1 was diffused in the cytoplasm. Predominant localization of BAI1 protein in a sub-cellular fraction enriched in growth cones indicated a possible role of BAI1 as a cell adhesion molecule inducing growth cone guidance. As a protein partner of BAI1, BAIAP2 may represent an important link between membrane and cytoskeleton in the process of neuronal growth.
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PMID:Identification of BAIAP2 (BAI-associated protein 2), a novel human homologue of hamster IRSp53, whose SH3 domain interacts with the cytoplasmic domain of BAI1. 1034 8


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