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

Tumor suppressor protein p53 is a potent transcriptional activator and regulates cell growth negatively. To characterize the transcriptional activation domain (TAD) of p53, various point mutants were constructed in the context of Gal4 DNA binding domain and tested for their transactivation ability. Our results demonstrated that the positionally conserved hydrophobic residues shared with herpes simplex virus VP16 and other transactivators are essential for transactivation. Also, the negatively charged residues and proline residues are necessary for full activity, but not essential for the activity of p53 TAD. Deletion analyses showed that p53 TAD can be divided into two subdomains, amino acids 1-40 and 43-73. An in vitro glutathione S-transferase pull-down assay establishes a linear correlation between p53 TAD-mediated transactivation in vivo and the binding activity of p53 TAD to TATA-binding protein (TBP) in vitro. Mutations that diminish the transactivation ability of Gal4-p53 TAD also impair the binding activity to TBP severely. Our results suggest that at least TBP is a direct target for p53 TAD and that the binding strength of TAD to TBP (TFIID) is an important parameter controlling activity of p53 TAD. In addition, circular dichroism spectroscopy has shown that p53 TAD peptide lacks any regular secondary structure in solution and that there is no significant difference between the spectra of the wild type TAD and that of the transactivation deficient mutant type.
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PMID:Transactivation ability of p53 transcriptional activation domain is directly related to the binding affinity to TATA-binding protein. 755 31

p53, the protein encoded by one of the most significant human tumor suppressor genes, is a sequence-specific transcriptional activator. When activated by a double-stranded DNA break, p53 function arrests cells in G1 and can induce apoptosis. Transcriptional activation function is critical for p53 tumor suppression, although transcriptional repressing and nontranscriptional functions of p53 may contribute. p53 activation requires that it bind to TFIID through interactions with TATA box-binding protein (TBP)-associated factors and potentially with TBP. Here, we studied the mechanism of p53 activation using in vitro transcription and a sufficiently high p53 concentration to squelch activated transcription. Squelching is thought to result when target molecules that interact with activation domains are titrated by binding to excess activator. Addition of either excess TFIIB or TFIID but not other proteins required for p53-activated transcription reversed squelching by high p53 concentrations, whereas neither stimulated transcription in reactions without excess p53. These results reveal that both TFIIB and TFIID are inhibited by high concentrations of p53 and suggest that p53 activation may work through direct or indirect interactions with both TFIIB and TFIID.
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PMID:Reversal of in vitro p53 squelching by both TFIIB and TFIID. 756 99

Murine tumor suppressor p53 is phosphorylated in the NH2-terminal transactivating domain at serines 9, 18, and 37. Change of any one of these serines to either alanine or aspartic acid did not alter p53 suppression of transformation of rat embryo fibroblasts by activated ras and E1A. Change of any two of these serines to alanines, however, led to a significant decrease in suppressor function. Substitution of alanines for all three serines caused the most severe loss of suppression and also reduced transactivation functions. The triple substitution had no apparent effects on intracellular accumulation or localization of p53, oligomerization, DNA binding, or interaction with the TFIID TATA-binding protein. In contrast, triple substitution of aspartic acid for serines 9, 18, and 37 had minimal effects on suppression and transactivation by p53. These results argue strongly that phosphorylation of serines 9, 18, and 37 facilitates the suppression and transactivation functions of p53.
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PMID:Serine phosphorylation in the NH2 terminus of p53 facilitates transactivation. 775 94

The p53 protein activates transcription of a target gene by binding to a specific DNA response element and interacting with the transcriptional apparatus of RNA polymerase II. The amino-terminal domain of p53 interacts with a component of the TFIID basal transcription complex. The human TATA-binding-protein-associated factor TAFII31, a component of TFIID, has been identified as a critical protein required for p53-mediated transcriptional activation. TAFII31 and p53 proteins bind to each other via amino acid residues in the amino-terminal domain of p53 that are essential for transcription. Antibodies directed against TAFII31 protein inhibit p53-activated but not basal transcription in vitro. These results demonstrate that TAFII31 is a coactivator for the p53 protein.
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PMID:Human TAFII31 protein is a transcriptional coactivator of the p53 protein. 776 66

A temperature-sensitive (ts) mutant of the BHK21 cell line derived from golden hamsters, tsBN462 has a mutation in the gene encoding the largest subunit of the TFIID complex, TAFII250/p230/CCG1, and arrests in the G1 phase at the nonpermissive temperature, 39.5 degrees C. We found that tsBN462 cells underwent apoptosis following growth arrest at 39.5 degrees C, suggesting a role for CCG1 as a repressor of apoptosis. By electron microscopic observation, tsBN462 cells at 39.5 degrees C showed characteristic features of apoptosis. Apoptosis was not suppressed by expression of Bc1-2 or the adenovirus E1B 19 kDa protein. Cell death was suppressed completely by expression of wild-type CCG1 and partially by wild-type p53, a growth suppressor protein. Cell cycle arrest induced by p53 may help survival of tsBN462 cells at 39.5 degrees C. Apoptosis was accelerated in SV40 large T antigen-transformed tsBN462 cells at 39.5 degrees C where SV40 large T antigen formed a complex with p53, implying that the apoptosis of tsBN462 cells at 39.5 degrees C occurred in a p53-independent manner. Our results suggest that CCG1/TAFII250 is required for the expression of factors regulating apoptosis.
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PMID:Apoptosis is induced in BHK cells by the tsBN462/13 mutation in the CCG1/TAFII250 subunit of the TFIID basal transcription factor. 779 84

Hepatitis B virus is a major risk factor in human hepatocellular carcinomas. We have used protein affinity chromatography to show that the 17-kDa hepatitis B virus gene product, HBx, binds directly to the human tumor suppressor gene product, p53. Interaction of HBx with p53 did not prevent p53 from specifically binding DNA. Instead, HBx enhanced p53's oligomerization state on a DNA oligonucleotide containing a p53 response element. Optimal binding of HBx to p53 required intact p53, but weaker binding to both the N-terminal activation domain of p53 and a protein fragment containing the C-terminal DNA-binding and oligomerization domains of p53 was observed. In transient transfection experiments with human Calu-6 cells, HBx inhibited transactivation by p53 of a reporter gene containing a p53 response element. Also, HBx inhibited p53-stimulated transcription in vitro even when added to the reaction mixture after the formation of the preinitiation complex. Interaction of HBx with p53 did not prevent the activation domain of p53 from binding two general initiation factors, the TATA-box binding protein subunit of TFIID and the p62 subunit of TFIIH. To explain these results, we propose that localization of HBx to a promoter by interaction with DNA-bound p53 enables a repression domain in HBx to directly contact the basal transcription machinery and thereby repress transcription.
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PMID:Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response element-directed transactivation. 785 26

Acidic transcriptional activation domains function well in both yeast and mammalian cells, and some have been shown to bind the general transcription factors TFIID and TFIIB. We now show that two acidic transactivators, herpes simplex virus VP16 and human p53, directly interact with the multisubunit human general transcription factor TFIIH and its Saccharomyces cerevisiae counterpart, factor b. The VP16- and p53-binding domains in these factors lie in the p62 subunit of TFIIH and in the homologous subunit, TFB1, of factor b. Point mutations in VP16 that reduce its transactivation activity in both yeast and mammalian cells weaken its binding to both yeast and human TFIIH. This suggests that binding of activation domains to TFIIH is an important aspect of transcriptional activation.
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PMID:Binding of basal transcription factor TFIIH to the acidic activation domains of VP16 and p53. 793 17

We show that wild-type human p53 transactivates the human epidermal growth factor receptor (EGFR) promoter in vivo in a dose-dependent manner, implicating p53 in promotion of cell proliferation. This activation is sensitive to the expression of cellular oncoprotein MDM2 and human papillomavirus type 18 (HPV-18) E6 protein. The p53 response element is localized within -15 and -569 of the promoter. The EGFR promoter does not have a TATA box, and has low activity in Saos-2 cells in the absence of p53. Results from our in vivo transient transfection assays suggest that p53-binding sites, without any other known promoter element, can act as bidirectional promoters in the presence of wild-type p53. Gel retardation analyses suggest that p53 may serve to nucleate TBP on a promoter. We propose that p53 successfully nucleates the transcription complex, possibly via direct interaction with TFIID, and activates the EGFR promoter.
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PMID:Wild-type human p53 activates the human epidermal growth factor receptor promoter. 815 94

The p53 tumor-suppressor gene product, a sequence-specific DNA-binding protein, has been shown to act both as a transcriptional activator and repressor in vivo and in vitro. Consistent with its roles in regulating transcription are recent observations that p53 binds directly to the TATA box-binding protein (TBP) subunit of the basal transcription factor TFIID. Here, we show that p53 cooperates with either recombinant TBP or partially purified TFIID in binding to a DNA fragment containing both a specific p53-binding site (RGC) and a TATA box (RGC-TATA). Surprisingly, both TBP and TFIID also stimulate p53 binding to DNA containing a specific p53-binding site but lacking a TATA box. These data are supported by the observation that p53 and Drosophila TBP combinatorily activate transcription in vivo. Our results suggest that p53 activates transcription through the formation of a more stable p53-TFIID-promoter complex. We also examined whether p53 might affect the ability of TBP or TFIID to interact with DNA containing a TATA box but lacking a p53-binding site. Although p53 strongly inhibited the interaction of TBP with such DNA, it had virtually no effect on TFIID binding. Thus, transcriptional repression by p53 may require additional functions other than inhibiting TBP binding.
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PMID:Cooperative DNA binding of p53 with TFIID (TBP): a possible mechanism for transcriptional activation. 840 94

The human p53 tumor suppressor gene product can activate transcription by RNA polymerase II in the yeast, Saccharomyces cerevisiae, as well as in human cells. Several viral transcriptional activator proteins have been shown to directly contact TBP, the TATA box-binding subunit of the general initiation factor, TFIID. In this report, we use protein affinity chromatography to show that the cellular transcription factor, p53, interacts directly and specifically with yeast TBP. The TBP binding domain of p53 was localized to its N-terminal 73 amino acids. This highly acidic portion of p53 functions as a transcriptional activation domain and is deleted in some tumors induced by the Friend leukemia virus. A human tumor-derived oncogenic point mutation of p53, which lies outside the activation domain of p53, but reduces its ability to activate transcription, greatly reduced the ability of p53 to bind yeast TBP in vitro. This mutation probably affects the overall conformation of the protein and indirectly interferes with the ability of p53 to contact TBP and activate transcription. In contrast, a mutated oncogenic form of p53 that is unaffected in its ability to activate transcription bound yeast TBP as well as wild type p53. The human TBP activity in a HeLa extract also bound to the activation domain of p53. Our data support a general model in which DNA-bound activator proteins activate transcription by interacting with TBP.
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PMID:Direct interaction between the transcriptional activation domain of human p53 and the TATA box-binding protein. 842 1


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