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)

B-Myb belongs to a family of related transcription factors which share a unique DNA binding domain. B-Myb plays an important role in regulation of the cell cycle. Its expression is upregulated by the human papilloma virus HPV16 E7 oncoprotein. Overexpression of B-Myb can bypass p53-mediated cell cycle arrest. The founding member of the myb gene family, c-Myb, and A-Myb are involved in hematopoiesis and neurogenesis, respectively, and are both activators of gene transcription. Whether B-Myb is a transactivator or a repressor, however, has remained a matter of discussion. We reviewed the transactivation potential of B-Myb in yeast, taking advantage of the fact that inducible gene activation is an evolutionarily conserved process. By mutational analysis we localized a conserved activation domain in B-Myb. In vertebrate cells the transactivation potential of B-Myb is concealed by the C-terminal part of the protein. We show that the cell cycle regulators cyclin A and cyclin E activate B-Myb by eradicating the inhibition mediated by its carboxy-terminus. Our data suggest that in vertebrates the trans-activating function of B-Myb is regulated during the cell cycle and link Myb functions to cell cycle progression.
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PMID:B-Myb, a repressed trans-activating protein. 942 11

HHV-6 genes and their functions that are unique and different from those of HCMV are summarized. HHV-6 encodes a HSV-1 UL9 homolog that is an origin-binding protein (OBP) essential for HSV-1 DNA replication, although HCMV has no clear homolog. The HHV-6 OBP binds to sequences with similarity to alpha-herpesvirus replication origin that lie within a genomic segment serving as an origin in transient assays. Consensus sequence for OBP binding, protein domain analyses and a model for OBP-origin interactions are described. HHV-6 encodes an AAV-2 rep homolog. Its transcript is expressed at low mRNA levels as a spliced transcript. The gene product suppresses both transformation by H.ras and transcription by HIV-1 promoters. HHV-6 specific transactivator gene DR7 exhibits malignant transforming activity and its protein binds to p53. Studies on IE-A locus and an HCMV UL69 homolog are also discussed.
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PMID:[Molecular biology of human herpesvirus 6: DNA replication and trans-activator genes]. 946 64

There are two ways of connecting Epstein-Barr virus (EBV) with the uncontrolled growth of EBV infected B lymphocytes: in case of evident immunosuppression when the control by cellular immunity is missing or in the case of pathological growth of malignant clone as a result of genetic translocations. Today, EBV is linked with the development of lymphomas in immunosuppressed patients, Hodgkin's and Burkitt's lymphoma and nasopharyngeal carcinoma. The presence of EBV genome in these patients can be confirmed in malignant cells, in lower or higher percent, as well as the high titers of antibodies against specific virus antigens. Hepatitis B viral infection (HBVI) of specific chronic course and associated with intensified inflammation and mitotic activity is of one of the most important factors in the appearance of hepatocellular carcinoma. Although the integration of viral DNA in DNA of hepatocytes has been one of the possible preconditions for carcinogenesis, recently a great attention has been paid to the inactivation of p53 suppressor gene, being a transcriptive transactivator. Other possible cofactors of carcinogenesis imply long-lasting viral replication, coinfection with HVB, HCV or HDV, interaction with other chemical carcinogens (hormones, aflatoxin, alcohol and similar). In distinction from other human DNA viruses, Hepatitis C virus (HCV) is a RNA virus which is not integrated in genome of hepatocyte and active replication of virus is maintained even when hepatocellular carcinoma is detected. It has been assumed that HCV inactivate or mutate the gene of tumor suppression p53 in an early stage of hepatocellular carcinoma development.
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PMID:[Epstein-Barr, hepatitis B and hepatitis C virus infections and their oncogenic potentials]. 947 11

Adenovirus type 5 E4 open reading frame 4 (E4orf4) protein has been previously shown to counteract transactivation of the junB and c-fos genes by cyclic AMP plus E1A protein and to interact with protein phosphatase 2A (PP2A). Here, we show that the wild-type E4orf4 protein induces apoptosis in the E1A-expressing 293 cells, in NIH 3T3 cells transformed with v-Ras, and in the lung carcinoma cell line H1299. The induction of apoptosis is not accompanied by enhanced levels of p53 in 293 cells and occurs in the absence of p53 in H1299 cells, indicating involvement of a p53-independent pathway. A mutant E4orf4 protein that had lost the ability to induce apoptosis also lost its ability to bind PP2A. We suggest that E4orf4 antagonizes continuous signals to proliferate, like those given by E1A or v-Ras, and that the conflicting signals lead to the induction of cell death.
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PMID:Adenovirus type 5 E4 open reading frame 4 protein induces apoptosis in transformed cells. 952 19

Overexpression of wild-type p53 in M1 myeloid leukemia cells induces apoptotic cell death that was suppressed by the calcium ionophore A23187 and the calcium ATPase inhibitor thapsigargin (TG). This suppression of apoptosis by A23187 or TG was associated with suppression of caspase activation but not with suppression of wild-type-p53-induced expression of WAF-1, mdm-2, or FAS. In contrast to suppression of apoptosis by the cytokines interleukin 6 (IL-6) and interferon gamma, a protease inhibitor, or an antioxidant, suppression of apoptosis by A23187 or TG required extracellular Ca2+ and was specifically abolished by the calcineurin inhibitor cyclosporin A. IL-6 induced immediate early activation of junB and zif/268 (Egr-1) but A23187 and TG did not. A23187 and TG also suppressed induction of apoptosis by doxorubicin or vincristine in M1 cells that did not express p53 by a cyclosporin A-sensitive mechanism. Suppression of apoptosis by A23187 or TG was not associated with autocrine production of IL-6. Apoptosis induced in IL-6-primed M1 cells after IL-6 withdrawal was not suppressed by A23187 or TG but was suppressed by the cytokines IL-6, IL-3, or interferon gamma. The results indicate that these Ca2+-mobilizing compounds can suppress some pathways of apoptosis suppressed by cytokines but do so by a different mechanism.
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PMID:Different mechanisms for suppression of apoptosis by cytokines and calcium mobilizing compounds. 953 84

The papillomavirus E2 proteins can function as sequence-specific transactivators or transrepressors of transcription and as cofactors in viral DNA replication. We previously demonstrated that acute expression of the bovine papillomavirus type 1 (BPV1) E2 protein in HeLa and HT-3 cervical carcinoma cell lines greatly reduced cellular proliferation by imposing a specific G1/S phase growth arrest. In this report, we analyzed the effects of a panel of point mutations in the BPV1 E2 protein to identify the functional requirements for acute growth inhibition. Disruption of E2-specific transactivation by mutations within either the transactivation domain or the DNA binding domain severely impaired E2-mediated growth inhibition in HeLa and HT-3 cells, even though these mutants retain various other E2 activities. This result indicates that functional transactivation activity is required for acute E2-mediated growth inhibition. HeLa cells, which contain a wild-type p53 gene, and HT-3 cells, which contain a transactivation-defective p53 gene, exhibited similar responses to the E2 mutants, suggesting that identical functions of the E2 protein were required for growth arrest regardless of p53 status. Replacement of the E2 transactivation domain with that of the herpes simplex virus VP16 generated a chimeric transactivator that efficiently stimulated expression of an E2-responsive reporter plasmid yet was completely defective for growth inhibition, suggesting that an E2-specific transactivation function is required for growth arrest. Surprisingly, the transactivation-defective E2 mutants were also markedly defective in their ability to repress transcription of the native human papillomavirus type 18 (HPV18) E6/E7 oncogenes in HeLa cells and of the HPV18 promoter present in a transfected reporter plasmid. These mutants were also defective in their ability to increase p53 levels. Therefore, efficient repression of the HPV18 promoter in HeLa cells is not merely a consequence of the binding of an E2 protein to appropriately situated binding sites in the promoter.
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PMID:Transactivation-competent bovine papillomavirus E2 protein is specifically required for efficient repression of human papillomavirus oncogene expression and for acute growth inhibition of cervical carcinoma cell lines. 955 78

p53 is required for hypoxia-induced apoptosis in vivo, although the mechanism by which this occurs is not known. Conversely, induction of the hypoxia-inducible factor-1 (HIF-1) transactivator stimulates transcription of a number of genes crucial to survival of the hypoxic state. Here we demonstrate that p53 represses HIF-1-stimulated transcription. Although higher levels of p53 are required to inhibit HIF than are necessary to transcriptionally activate p53 target genes, these levels of p53 are similar to those that stimulate cleavage of poly(ADP-ribose) polymerase, an early event in apoptosis. Transfection of full-length p300 stimulates both p53-dependent and HIF-dependent transcription but does not relieve p53-mediated inhibition of HIF. In contrast, a p300 fragment, which binds to p53 but not to HIF-1, prevents p53-dependent repression of HIF activity. Transcriptionally inactive p53, mutated in its DNA binding domain, retains the ability to block HIF transactivating activity, whereas a transcriptionally inactive double point mutant defective for p300 binding does not inhibit HIF. Finally, depletion of doxorubicin-induced endogenous p53 by E6 protein attenuates doxorubicin-stimulated inhibition of HIF, suggesting that a p53 level sufficient for HIF inhibition can be achieved in vivo. These data support a model in which stoichiometric binding of p53 to a HIF/p300 transcriptional complex mediates inhibition of HIF activity.
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PMID:p53 inhibits hypoxia-inducible factor-stimulated transcription. 957 38

Understanding how alterations in growth control pathways are translated into changes in the cell cycle regulatory machinery is a major challenge for understanding the development of human cancers. The ability of both tumor suppressor proteins, p53 and BRCA1, to induce the expression of p21(WAF1/Cip1) in combination with the inhibitory activity of p21(WAF1/Cip1) against cyclin-dependent kinases suggests that the regulation of p21(WAF1/Cip1) expression is an important aspect of mammalian cell cycle growth control. To elucidate the role of serine/threonine protein phosphatase type 5 (PP5) in processes regulating cell cycle progression, we developed antisense oligodeoxynucleotides targeted against PP5 (e.g. ISIS 15534) that specifically inhibit PP5 gene expression. Employing ISIS 15534, we demonstrate that the specific inhibition of PP5 gene expression has a marked antiproliferative effect on cells, characterized by induction of p21(WAF1/Cip1) and the subsequent arrest of cell growth. Investigations into the mechanisms leading to growth arrest reveal that, in the absence of PP5, the expression of p21(WAF1/Cip1) is induced in p53-competent A549 cells but not in p53 protein-deficient T-24 cells. Employing a stable cell line derived from p53-deficient human fibroblast that contains tetracycline-regulated transactivator and operator plasmids to control the expression of wild-type p53 (TR9-7 cells), we then show that the induction of p21(WAF1/Cip1), which occurs in response to the inhibition of PP5 expression, requires the p53 protein. Additional studies indicate that PP5 acts upstream of p53, influencing both the phosphorylation state and the ability of p53 to bind DNA, without causing an increase in p53 gene transcription. Together these studies suggest that PP5 is a regulatory component of a signaling pathway that affords replicating cells G1 checkpoint growth control and that it is the regulation of PP5 that, in turn, controls p53-mediated expression of p21(WAF1/Cip1) and growth arrest in this pathway. In addition, since the inhibition of PP5 gene expression has marked antiproliferative activity and the overexpression of p21(WAF1/Cip1) blocks the growth of tumor cells, these studies suggest that compounds that inhibit of PP5 gene expression may be useful in the treatment of human cancers.
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PMID:Serine/threonine protein phosphatase type 5 acts upstream of p53 to regulate the induction of p21(WAF1/Cip1) and mediate growth arrest. 957 75

Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) transforms human T cells in vitro, and Tax, a potent transactivator of viral and cellular genes, plays a key role in cell immortalization. Tax activity is mediated by interaction with cellular transcription factors including members of the CREB/ATF family, the NF-kappaB/c-Rel family, serum response factor, and the coactivators CREB binding protein-p300. Although p53 is usually not mutated in HTLV-1-infected T cells, its half-life is increased and its function is impaired. Here we report that transient coexpression of p53 and Tax results in the suppression of p53 transcriptional activity. Expression of Tax abrogates p53-induced G1 arrest in the Calu-6 cell line and prevents the apoptosis induced by overexpressing p53 in the HeLa/Tat cell line. The Tax mutants M22 and G148V, which selectively activate the CREB/ATF pathway, exert these same biological effects on p53 function. In contrast, the NF-kappaB-active Tax mutant M47 has no effect on p53 activity in any of these systems. Consistent with the negative effect of Tax on p53, no activity on a p53-responsive promoter was observed upon transfection of HTLV-1-infected T-cell lines. The p53 protein is expressed at high levels in the nucleus, and nuclear extracts of HTLV-1-infected T cells bind constitutively to a DNA oligonucleotide containing the p53 response element, indicating that Tax does not interfere with p53 binding to DNA. Tax is able to suppress the transactivation function of p53 in three different cell lines, and this suppression required Tax-mediated activation of the CREB/ATF, but not the NF-kappaB/c-Rel, pathway. Tax and the active Tax mutants were able to abrogate the G1 arrest and apoptosis induced by p53, and this effect does not correlate with an altered localization of nuclear p53 or with the disruption of p53-DNA complexes. The suppression of p53 activity by Tax could be important in T-cell immortalization induced by HTLV-1.
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PMID:Human T-cell lymphotropic/leukemia virus type 1 Tax abrogates p53-induced cell cycle arrest and apoptosis through its CREB/ATF functional domain. 976 30

The hepatitis B virus protein HBx is a promiscuous transactivator implicated in both cell growth and death and in the development of hepatocellular carcinoma. We recently reported that HBx can potentiate c-myc-induced liver oncogenesis in a transgenic model where low level expression of HBx induces no pathology. To assess if HBx could affect the hepatocyte turnover, we investigated the HBx-elicited apoptotic responses in transgenic livers and in primary hepatocyte cultures. Here we show that transgenic expression of HBx is associated with a twofold increase of spontaneous cell death in the mouse liver. The finding that apoptosis was enhanced to similar extents in HBx mice carrying homozygous p53 null mutations implied that functionally intact p53 was not required to transduce the death signal. A direct, dose-dependent apoptotic function of HBx was demonstrated in transient transfections of liver-derived cell lines. We further show that stable expression of HBx at low, presumably physiological levels in primary hepatocytes, induced cellular susceptibility to diverse apoptotic insults, including growth factor deprivation, treatment with anti-Fas antibodies or doxorubicine and oxidative stress. HBx expression, but not p53 status profoundly affected the commitment of cells to die upon apoptotic stimuli. These data strengthen the notion that HBX may contribute to HBV pathogenesis by enhancing apoptotic death in the chronically infected liver.
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PMID:p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro. 979 83


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