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

There is now much evidence to suggest that the p53 tumour suppressor protein functions to monitor the integrity of the genome. When DNA damage is detected, p53 suppresses cell growth to allow repair or directs the cell into apoptosis. The mechanism of action of p53 is as yet unclear but recent evidence has accumulated to suggest that p53 might act by regulating gene expression. Consistent with this model, p53 can both activate and repress a number of viral and cellular promoters. p53 has also been shown to bind to the CCAAT-binding Factor and TATA-binding protein (TBP), and there is direct evidence that p53 represses in vitro transcription by preventing TBP from binding DNA. We now provide evidence that p53 can repress transcription from the SV40 promoter by disrupting DNA/protein complexes involving transcription factor Sp1.
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PMID:p53 represses SV40 transcription by preventing formation of transcription complexes. 747 50

Tumor necrosis factor alpha (TNF) is a potent activator of transcription directed by the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). We have recently reported that the p53 tumor suppressor gene product binds to a site within the Sp1 binding region of the HIV-1 LTR and contributes to the TNF induction of this promoter. In this study we show that the transcription factor Sp1 cooperates with p53 in the transcriptional activation directed by the HIV-1 LTR. The presence of Sp1 increased p53 binding to its recognition sequence in the HIV-1 LTR, and experiments in Drosophila cells show that Sp1 is necessary for full transactivation by mutant p53. Importantly, TNF induced the association between p53 and Sp1 in Jurkat T cells. These data demonstrate a synergistic role for these proteins in the mechanism of TNF induction of HIV-1 LTR-mediated transcription and suggest that Sp1 may play an important role in modulating certain functions of p53.
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PMID:p53 and Sp1 interact and cooperate in the tumor necrosis factor-induced transcriptional activation of the HIV-1 long terminal repeat. 764 77

The Waf1/Cip1 protein induces cell cycle arrest through inhibition of the activity of cyclin-dependent kinases and proliferating cell nuclear antigen. Expression of the WAF1/CIP1 gene is induced in a p53-dependent manner in response to DNA damage but can also be induced in the absence of p53 by agents such as growth factors, phorbol esters, and okadaic acid. WAF1/CIP1 expression in U937 human leukemic cells is induced by both phorbol ester, a protein kinase C activator, and by okaidaic acid, an inhibitor of phosphatases 1 and 2A. Both of these agents induce the differentiation of these leukemic cells toward macrophages. We demonstrate that phorbol esters and okadaic acid stimulate transcription from the WAF1/CIP1 promoter in U937 cells. This transcription is mediated by a region of the promoter between -154 and +16, which contains two binding sites for the transcription factor Sp1. Deletion or mutation of these Sp1 sites reduces WAF1/CIP1 promoter response to phorbol ester and okadaic acid, while a reporter gene under the control of a promoter containing only multiple Sp1 binding sites and a TATA box is induced by phorbol ester and okadaic acid. The WAF1/CIP1 promoter is also highly induced by exogenous Sp1 in the Sp1-deficient Drosophila Schnieder SL 2 cell line. These results suggest that phorbol ester and okadaic acid activate transcription of the WAF1/CIP1 promoter through a complex of proteins that includes Sp1 and basal transcription factors.
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PMID:The role of the transcription factor Sp1 in regulating the expression of the WAF1/CIP1 gene in U937 leukemic cells. 855 3

Previous studies indicated a high affinity of the transcription factor Sp1 for DNA adducts derived from benzo[a]pyrene diol epoxide (BPDE) in sequences that are not normal binding sites for Sp1. We tested for functional effects of this phenomenon in three systems in which transcription is Sp1-dependent. In an in vitro, Sp1-dependent transcription system addition of heterologous plasmid DNA containing BPDE adducts abolished production of a specific run-off transcript. This inhibition was not seen with unmodified plasmid DNA, and could be overcome by addition of purified Sp1 protein. In SL2 insect cells, high-level expression of an Sp1-dependent reporter gene, which was dependent on co-transfection of an Sp1 expression vector, was inhibited >95% by co-transfection of heterologous DNA containing BPDE adducts. This inhibition could be partially overcome by increasing the amount of the Sp1 expression vector in the transfections. In human C33A cells, expression of a transfected reporter gene driven by a GC box containing fragment of the human E2F1 promoter was enhanced by co-transfection of an Sp1 expression plasmid. Expression was inhibited 3-6-fold by co-transfection of heterologous DNA containing BPDE-DNA adducts. A similar inhibition was seen in human SAOS-2 cells, which lack functional p53 protein. These data are consistent with functionally significant sequestration of the Sp1 transcription factor by BPDE-DNA adducts in all three systems. Altered availability of transcription factors such as Sp1 in carcinogen-treated cells may disrupt patterns of gene expression.
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PMID:Disruption of transcription in vitro and gene expression in vivo by DNA adducts derived from a benzo[a]pyrene diol epoxide located in heterologous sequences. 905 13

The induction of the transcription factor Sp1 by prolactin (PRL) and interleukin-2 (IL-2) was investigated in the PRL- and IL-2 responsive rat Nb2 T-cell line. Western analysis showed a rapid increase in Sp1 synthesis in Nb2 cells in response to PRL or IL-2. Elevation of Sp1 protein levels occurred within 15 min following PRL or IL-2 stimulation, reached a maximum by 1 h and was inhibited by cycloheximide, indicating de novo protein synthesis. Interestingly, dilution of confluent, growth-arrested Nb2 cells to low density also caused a rapid elevation in Sp1 suggesting that growth arrest may down-regulate Sp1 synthesis. Electrophoretic mobility shift assays using an Sp1 consensus oligonucleotide as probe showed a rapid but transient formation of a single PRL-inducible complex at 30 min. In contrast, three IL-2-inducible complexes were formed at 30 min and persisted to at least 60 min. Mobility shift interference assays using specific Stat antibodies failed to detect Stat1alpha, Stat3 or Stat5 in the 30 min PRL-inducible complex. In contrast, the IL-2 induced complexes contained Stat3 alone at 30 min and both Stat3 and Stat5 at 60 min. The PRL- and IL-2-inducible complexes did not contain the tumor suppressor protein, p53. The time dependent association of the Stat proteins with the IL-2-inducible complexes, but not with the PRL-inducible complex, suggests that the two mitogens may selectively utilize specific promoter elements for transcriptional activation of PRL- and IL-2-responsive genes. Alternatively, the two mitogens may be activating different genes with Sp1-binding promoter elements for their mitogenic action in Nb2 cells.
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PMID:Induction of Sp1 activity by prolactin and interleukin-2 in Nb2 T-cells: differential association of Sp1-DNA complexes with Stats. 917 24

The HIV-LTR region contains binding sites for, and is regulated by, a number of transcription factors including Sp1 and NF-kB. The wild-type p53 tumor suppressor protein represses transcription from the HIV-LTR promoter while oncogenic mutant forms of p53 stimulate expression from the HIV-LTR. We have shown previously that wild-type p53 is a site specific DNA binding protein that binds to a region of the SV40 virus which contains GC-box DNA binding sites for the ubiquitously expressed transcription factor Sp1. In this study using DNase I footprinting, we have shown that purified p53 is able to protect the Sp1 binding sites and the adjacent NF-kB site of the HIV-LTR. Furthermore we have demonstrated that when p53 and Sp1 are mixed together both proteins change each other's interaction with DNA. Interestingly, we noted that oncogenic mutant p53 is also able to change the interaction of Sp1 with DNA. We confirmed p53 dependent repression of HIV-LTR driven transcription by comparing the expression from an HIV-LTR reporter construct in the presence and absence of p53. EMSA of an oligonucleotide sequence derived from the HIV-LTR sequence demonstrated a slight decrease in Sp1 DNA binding activity with nuclear extract derived from the cell line expressing a high level of wild-type p53. These data suggest that the influence of p53 on the transcription of promoters with Sp1 binding sites may be partially due to a change in the DNA binding ability of Sp1.
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PMID:p53 represses Sp1 DNA binding and HIV-LTR directed transcription. 944 26

The cell cycle inhibitor protein p21(WAF1/Cip1) (p21) is a critical downstream effector in p53-dependent mechanisms of growth control and p53-independent pathways of terminal differentiation. We have recently reported that the transforming growth factor-beta pathway-specific Smad3 and Smad4 proteins transactivate the human p21 promoter via a short proximal region, which contains multiple binding sites for the ubiquitous transcription factor Sp1. In the present study we show that the Sp1-occupied promoter region mediates transactivation of the p21 promoter by c-Jun and the related proteins JunB, JunD, and ATF-2. By using gel electrophoretic mobility shift assays we show that this region does not contain a binding site for c-Jun. In accordance with the DNA binding data, c-Jun was unable to transactivate the p21 promoter when overexpressed in the Sp1-deficient Drosophila-derived SL2 cells. Coexpression of c-Jun and Sp1 in these cells resulted in a strong synergistic transactivation of this promoter. In addition, a chimeric promoter consisting of six tandem high affinity Sp1-binding sites fused with the CAT gene was transactivated by overexpressed c-Jun in HepG2 cells. The above data propose functional cooperation between c-Jun and Sp1. Physical interactions between the two factors were demonstrated in vitro by using GST-Sp1 hybrid proteins expressed in bacteria and in vitro transcribed-translated c-Jun. The region of c-Jun mediating interaction with Sp1 was mapped within the basic region leucine zipper domain. In vivo, functional interactions between c-Jun and Sp1 were demonstrated using a GAL4-based transactivation assay. Overexpressed c-Jun transactivated a chimeric promoter consisting of five tandem GAL4-binding sites only when coexpressed with GAL4-Sp1-(83-778) fusion proteins in HepG2 cells. By utilizing the same assay, we found that the glutamine-rich segment of the B domain of Sp1 (Bc, amino acids 424-542) was sufficient for c-Jun-induced transactivation of the p21 promoter. In conclusion, our data support a mechanism of superactivation of Sp1 by c-Jun, which is based on physical and functional interactions between these two transcription factors on the human p21 and possibly other Sp1-dependent promoters.
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PMID:c-Jun transactivates the promoter of the human p21(WAF1/Cip1) gene by acting as a superactivator of the ubiquitous transcription factor Sp1. 1050 25

Our recent studies (R. Pollock et al., Clin. Cancer Res., 4: 1985-1994, 1998; M. Milas et al., Cancer Gene Ther., in press, 2000) have shown that the restoration of wild-type (wt) p53 enhances cell cycle control in vitro and inhibits the growth of human soft-tissue sarcoma in severe combined immunodeficient mice. We hypothesized that the antitumor effect of wt p53 overexpression in sarcoma cells is attributable not only to enhanced cell cycle control but also to inhibition of angiogenesis. We evaluated the effect of restoring wt p53 function on angiogenesis in human soft-tissue sarcoma harboring mutant p53. Restoration of wt p53 expression in human leiomyosarcoma SKLMS-1 cells that contain mutant p53 markedly inhibited angiogenesis induced by tumor cells in vivo. Angiogenesis assays using an in vivo Matrigel plug assay demonstrated that less neovascularization in severe combined immunodeficient mice was observed with conditioned medium (CM) from human synovial sarcoma cells expressing wt p53 compared with CM from human synovial sarcoma cells expressing mutant p53. Microvessel density and microvessel counts were lower in tumor xenografts from cells containing wt p53 than in tumor xenografts from cells containing mutant p53. The growth and migration of murine lung endothelial cells were decreased when cells were treated with CM from sarcoma cells expressing wt p53 compared with CM from sarcoma cells expressing mutant p53. The introduction of wt p53 into sarcoma cells containing mutant p53 significantly reduced the expression of vascular endothelial growth factor (VEGF), which is a key mediator of tumor angiogenesis. Stimulation of endothelial cell migration by CM from cells expressing mutant p53 was significantly reduced after anti-VEGF neutralizing antibody was added to the CM. Using luciferase as the reporter of VEGF promoter activity, we found that wt p53 inhibited VEGF promoter activity in SKLMS-1 cells. Deletion analysis defined an 87-bp region (bp -135 to -48) in the VEGF promoter that is necessary for inhibiting VEGF promoter activity by wt p53. The transcription factor Sp1 may be involved in the repression of VEGF promoter activity by wt p53 in SKLMS-1 cells. These data indicated that wt p53 can suppress angiogenesis in human soft-tissue sarcomas by transcriptional repression of VEGF expression.
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PMID:Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. 1091 82

Aflatoxin B1 (AFB1) induced mutation of the p53 gene at codon 249 (p53mt249) is critical during the formation of hepatocellular carcinoma (HCC) following hepatitis B virus (HBV) infection. p53mt249 markedly increases insulin-like growth factor II (IGF-II) transcription largely from promoter 4, accumulating the fetal form of IGF-II. Modulation of the transcription factor binding to IGF-II P4 by wild-type p53 and p53mt249 was identified. Wild-type p53 inhibited binding of transcription factors Sp1 and TBP on the P4 promoter, while p53mt249 enhanced the formation of transcriptional complexes through enhanced DNA-protein (Sp1 or TBP) and protein-protein (Sp1 and TBP) interactions. p53mt249 stimulates transcription factor Sp1 phosphorylation which might be a cause of increased transcription factor binding on the P4 promoter while wild-type p53 does not. Transfection of hepatocytes with p53mt249 impaired induction of apoptosis by the HBV-X protein and TNF-alpha. Therefore, the blocking of apoptosis through enhanced production of IGF-II should provide a favorable opportunity for the selection of transformed hepatocytes. These results explain the molecular basis for the genesis of HCC by p53mt249 which was found to be induced by a potent mutagen, AFB1.
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PMID:Activation of the insulin-like growth factor II transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma. 1094 25

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


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