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)

Overexpression of the tumor suppressor p53 in HeLa cells leads to loss of the estradiol- and genistein-induced human estrogen receptor (ERalpha) transactivity. The coactivator p300, which binds to both ERalpha and p53, does not prevent this loss of hERalpha function. In this report we demonstrate that p53 physically binds to multiple domains of the hERalpha. This binding did not interfere with either the ERalpha dimerization or the interaction between hERalpha and its coactivator SRC-1. However, p53 did interfere with the hERalpha-ERE binding. These results may explain how p53 down-regulates the expression of some estrogen-responsive genes such as c-fos, c-jun, TPA, and bcl-2. This study supports the cross-talk between the p53 and the ERalpha signaling pathways.
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PMID:p53 down-regulates ER-responsive genes by interfering with the binding of ER to ERE. 1052 69

The tumor suppressor protein p53 exerts its cell cycle-regulatory effects through its ability to function as a sequence-specific DNA-binding transcription factor. Herein, we show that p53 physically interacts with specific subregions of steroid receptor coactivator-1 (SRC-1) and its family members, p/CIP (p300/CBP interacting protein), xSRC-3, and AIB1 (amplified in breast cancer), originally isolated as transcription coactivators of nuclear receptors, as demonstrated by the yeast and mammalian two-hybrid tests as well as glutathione S-transferase pull-down assays. Interestingly, cotransfection of HeLa cells with SRC-1- or p/CIP expression vector potentiated the p53-mediated transactivation, whereas AIB1 and xSRC-3 were repressive. All of these SRC-1 members, however, similarly stimulated transactivation mediated by nuclear receptors and AP-1, as previously described. These results suggest that SRC-1 and its family members may differentially modulate the p53 transactivation in vivo.
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PMID:Steroid receptor coactivator-1 and its family members differentially regulate transactivation by the tumor suppressor protein p53. 1055 85

The p53 tumour suppressor protein is a labile transcription factor that is activated and stabilized in response to a wide range of cellular stresses, through a mechanism involving disruption of its interaction with MDM2, a negative regulatory partner. Induction of p53 by DNA damage additionally involves a series of phosphorylation and acetylation modifications, some of which are thought to regulate MDM2 binding. Here we report the effects of introducing mutations at several known or putative N-terminal phosphorylation sites on the transactivation function of p53. These studies highlight phosphorylation of Ser15, a key phosphorylation target during the p53 activation process, as being critical for p53-dependent transactivation. Biochemical data indicate that the mechanism by which phosphorylation of Ser15 stimulates p53-dependent transactivation occurs through increased binding to the p300 coactivator protein. The data also indicate that Ser15-dependent regulation of transactivation is independent of any involvement in modulating MDM2 binding, and that Ser15 phosphorylation alone is not sufficient to block the p53-MDM2 interaction.
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PMID:Serine15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2. 1060 Oct 22

The promoter of the human proliferating cell nuclear antigen (PCNA) gene is activated by the adenovirus oncoprotein E1A 243R in HeLa cells. To understand the effect of this oncoprotein on PCNA expression in cells that are sensitive to oncogenic transformation by adenovirus, we studied the effect of E1A 243R on PCNA promoter-directed reporter gene expression in cloned rat embryo fibroblast (CREF) and primary baby rat kidney cells. In contrast to the results obtained in HeLa cells, E1A repressed the PCNA promoter in both cell-types. Promoter analysis identified a p53-responsive element that mediates E1A-induced repression. Repression required the intact N-terminus of E1A 243R, as shown by the ability of mutant E1A proteins to repress the promoter, and correlated with the p300-binding region of E1A. The adenovirus E1B 19K protein relieved repression by E1A 243R. These results reveal dual pathways for induction of this essential DNA replication factor and suggest a mechanism for oncogenic cooperativity between the E1A and E1B oncoproteins.
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PMID:Dual action of the adenovirus E1A 243R oncoprotein on the human proliferating cell nuclear antigen promoter: repression of transcriptional activation by p53. 1061 24

We have reported that histone acetylation induced by trichostatin A (TSA) promotes p21(waf1/cip1) (p21) expression, the GC-box located just upstream of TATA box was responsible for TSA-induced promoter activation, and both Sp1 and Sp3 were the working activator of this GC-box. To understand the molecular pathway from histone acetylation to this Sp1 family factors-mediated promoter activation, we investigated the function of p300, one of the histone acetyltransferase, in the present work. The evidence supporting the linkage between p300 and TSA-induced p21 promoter activation were realized from the following findings: 1) cotransfection of p300 elevated p21 promoter activity, and this elevation was dependent on TSA-responsive GC-box; 2) TSA-induced promoter activation was blocked by the introduction of p300 dominant-negative mutant into cells; and 3) Sp1- or Sp3-mediated activation was also suppressed by this p300 dominant-negative mutant. Our data also suggested that p300 collaborates with Sp1 in a way which is different from that when p300 collaborates with p53 in p21 transcription.
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PMID:p300 collaborates with Sp1 and Sp3 in p21(waf1/cip1) promoter activation induced by histone deacetylase inhibitor. 1062 87

The newly identified p53 homolog p73 mimics the transcriptional function of p53. We have investigated the regulation of p73's transcriptional activity by p300/CREB binding protein (CBP). p73-p300 complexes were identified in HeLa cell extracts by cofractionation and coimmunoprecipitation assays. The p73-p300 interaction was confirmed in vitro by glutathione S-transferase-protein association assays and in vivo by coimmunoprecipitating the overexpressed p300 and p73 in human p53-free small-cell lung carcinoma H1299 or osteosarcoma Saos-2 cells. The N terminus but not the N-terminal truncation of p73 bound to the CH1 domain (amino acids [aa] 350 to 450) of p300/CBP. Accordingly, this p73 N-terminal deletion was unable to activate transcription or to induce apoptosis. Overexpression of either p300 or CBP stimulated transcription mediated by p73 but not its N-terminally deleted mutant in vivo. The N-terminal fragment from aa 19 to 597, but not the truncated fragment from aa 242 to 1700 of p300, reduced p73-mediated transcription markedly. p73-dependent transcription or apoptosis was partially impaired in either p300- or CBP-deficient human breast carcinoma MCF-7 or H1299 cells, suggesting that both coactivators mediate transcription by p73 in cells. These results demonstrate that the N terminus of p73 directly interacts with the N-terminal CH1 domain of p300/CBP to activate transcription.
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PMID:The N-terminal domain of p73 interacts with the CH1 domain of p300/CREB binding protein and mediates transcriptional activation and apoptosis. 1064 16

p53 phosphorylation and association with proteins is implicated in its stability and activity. We have compared the association of DNA-bound and overall pools of p53 with murine double minute 2 (Mdm2), c-Jun NH2-terminal kinase (JNK), p300/CBP, and p14ARF during cell cycle progression. Whereas DNA-bound p53 associates with JNK at G0-G1 and with Mdm2 and p300 during S and G2-M phases, the general pool of p53 was found in complex with JNK and Mdm2 almost throughout the cell cycle. Phosphorylation of p53 at serines 9, 15, and 20 is at the highest levels at G1 and at serines 37 and 392 during G2-M phase. Whereas a high dose of UV irradiation was required for phosphorylation of serines 15 and 392 between 8 and 24 h after treatment, a low dose caused immediate phosphorylation on serines 9, 20, and 372. These dynamic changes in the phosphorylation of p53 are expected to play a pivotal role in p53 association, stability, and function.
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PMID:p53 phosphorylation and association with murine double minute 2, c-Jun NH2-terminal kinase, p14ARF, and p300/CBP during the cell cycle and after exposure to ultraviolet irradiation. 1070 2

Induction of apoptosis seems to be a key function in maintaining normal cell growth by exerting negative controls on cell proliferation and suppressing tumorigenesis. The adenovirus E1A oncogene shows both cell cycle progression and apoptotic functions. To understand the mechanism of E1A-induced apoptosis, the apoptotic function of E1A 13S was investigated in p53-null cells. We show here that E1A is sufficient by itself to induce substantial apoptosis independent of p53 and other adenoviral genes. The apoptotic function of E1A is accompanied by processing of caspase-3 and cleavage of poly(ADP-ribose)-polymerase. Cell death is significantly blocked by the caspase inhibitor zVAD-fmk and when coexpressed with E1B19K, Bcl-2 or the retinoblastoma protein (RB). Analyses of E1A mutants indicated that the apoptotic activity of E1A correlates closely with the ability to bind the key regulators of E2F1-induced apoptosis, p300 and RB. Finally, in vivo relevance of down-modulation of p53-independent apoptosis for efficient transformation is demonstrated.
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PMID:E1A is sufficient by itself to induce apoptosis independent of p53 and other adenoviral gene products. 1071 32

The transcriptional coactivators p300 and CREB binding protein (CBP) are important regulators of the cell cycle, differentiation, and tumorigenesis. Both p300 and CBP are targeted by viral oncoproteins, are mutated in certain forms of cancer, are phosphorylated in a cell cycle-dependent manner, interact with transcription factors such as p53 and E2F, and can be found complexed with cyclinE-Cdk2 in vivo. Moreover, p300-deficient cells show defects in proliferation. Here we demonstrate that transcriptional activation by both p300 and CBP is stimulated by coexpression of the cyclin-dependent kinase inhibitor p21(WAF/CIP1). Significantly this stimulation is independent of both the inherent histone acetyltransferase (HAT) activity of p300 and CBP and of the previously reported carboxyl-terminal binding site for cyclinE-Cdk2. Rather, we describe a previously uncharacterized transcriptional repression domain (CRD1) within p300. p300 transactivation is stimulated through derepression of CRD1 by p21. Significantly p21 regulation of CRD1 is dependent on the nature of the core promoter. We suggest that CRD1 provides a novel mechanism through which p300 and CBP can switch activities between the promoters of genes that stimulate growth and those that enhance cell cycle arrest.
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PMID:A novel transcriptional repression domain mediates p21(WAF1/CIP1) induction of p300 transactivation. 1073 70

Retinoic acid (RA) has been shown to be effective in suppressing premalignant lesions and preventing second primary malignancies in patients cured of squamous cell carcinoma of the head and neck. However, the precise mechanisms of these effects are still uncertain. In the present study, we examined the effect of 9-cis-RA on the growth of six oral cancer cell lines (HSC-2, HSC-3, HSC-4, Ca9-22, Ho-1-N-1 and Ho-1-u-1). In addition, the relationship among growth and differentiation of tumor cells, RA responsiveness and the expression of nuclear retinoic acid receptors were also investigated. Among the six cell lines examined, five (HSC-2, HSC-3, HSC-4, Ca9-22 and Ho-1-u-1) displayed growth inhibition after treatment with 1x10(-6) M 9-cis-RA, while Ho-1-N-1 cells were resistant to 9-cis-RA. The expression level of RARbeta in 9-cis-RA resistant Ho-1-N-1 cells was very low in comparison with the sensitive cell lines. On the other hand, all of the six the cell lines expressed RARalpha, RARgamma, and RXRalpha at various levels. 9-cis-RA induced accumulation of cell population in G1 phase in HSC-3 cells on the 6th day of the treatment, followed by a marked reduction in the levels of hyperphosphorylated pRB, whereas p53 level was not altered. Interestingly, 9-cis-RA induced transiently the expression of p21(Waf1/Cip1), p27(Kip1), p300, CBP, BAX, Bak and bcl-2 proteins, respectively. This effect was associated with reduction of cyclin D1, cdk4 and CDK-activating kinase (cyclin H and cdk7) protein in HSC-3 cells. These results suggest that the growth inhibitory effect of 9-cis-RA on oral squamous cell carcinoma may depend on the expression levels of RARs, especially RARbeta proteins and RXRalpha proteins, and that 9-cis-RA may provide a powerful therapeutic agent for head and neck cancers.
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PMID:Effect of 9-cis-retinoic acid on oral squamous cell carcinoma cell lines. 1073 15


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