Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumor suppressor protein is a transcriptional activator, which can mediate apoptotic cell death in a variety of cell types. To determine whether sequence-specific trans-activation is a prerequisite for the induction of apoptosis by p53, the apoptotic effects of various p53 deletion mutants were monitored in an assay based on the transient transfection of HeLa cells. A truncated protein (p53dl214), containing only the first 214 amino-terminal residues of murine p53, induced extensive apoptosis, albeit at a slower rate than trans-activation-competent wild-type p53. p53dl214 also suppressed the transformation of rat fibroblasts by several oncogene combinations and particularly by myc plus ras and HPV E7 plus ras. p53dl214 lacks a major portion of the DNA-binding domain and cannot activate p53-responsive promoters. Moreover, a human p53 protein carrying mutations in residues 22 and 23 also triggered HeLa cell apoptosis, despite failing to induce significant activation of relevant p53 target promoters. These data suggest the existence of two p53-dependent apoptotic pathways--one requiring activation of specific target genes, and the other independent of sequence-specific trans-activation. The latter pathway may actually be totally uncoupled from the binding of p53 to its consensus DNA sites. The relative contribution of trans-activation-independent apoptosis to tumor suppression by p53 may be dictated by the specific genetic lesions present in the particular tumor.
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PMID:Induction of apoptosis in HeLa cells by trans-activation-deficient p53. 765 68

The ability of p53 to act as a tumor suppressor is tightly correlated with its ability to function as a transcriptional activator at the G1/S-phase cell cycle checkpoint. Previous overexpression studies have indicated simultaneous induction of p53 target genes, despite opposing cellular functions of their protein products. To delineate the response of endoansactivation function to DNA damage in a normal cell, we irradiated early-passage rat embryo fibroblasts with 10 or 50 J/m2 of ultraviolet light (mostly UV-C). We investigated the induction of p53 targets and the response of the cells over 48 h. In this system, northern analysis revealed differential regulation of the p53 targets p21WAFI/CIPI, Mdm2, Ccng (also known as cyclin G) and Bax in accordance with their proposed functions in the cell. The growth suppressor p21WAFI/CIPI was activated initially (within 6 h) after exposure to 10 J/m2, but not after 50 J/m2, in a p53-dependent manner. Both Ccng and Mdm2 were activated later than p21 (12-24 h) after exposure to 10 J/m2. Expression of Bax was increased after exposure to both 10 J/m2 (24 h after UV exposure) and 50 J/m2 (6 h after UV exposure), which correlated well with the apoptosis seen in cells exposed to either dose. These fibroblasts also exhibited a temporary cell cycle arrest (< 8 h) at 10 J/m2. Thus we have investigated the physiological response of the p53 pathway in normal cells and identified a temporal order for induction of p53 targets. We demonstrate that both apoptosis and cell cycle arrest occur simultaneously when cells are treated with UV radiation, indicating that the amount of DNA damage is not the sole determinant of the cellular response.
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PMID:Differential activation of p53 targets in cells treated with ultraviolet radiation that undergo both apoptosis and growth arrest. 925 29

p51/p63 is a novel p53 homologue that has been shown to act as a transcriptional activator through the p53-binding sequence of the p21/WAF1 promoter and to induce apoptosis when it is expressed transiently in a human tumor cell line. We developed transcription assay systems for these two related genes in both Saccharomyces cerevisiae and mammalian cells and used them to investigate the functional similarities and differences of these genes. We found that p51/p63 trans-activated the previously identified p53 target genes, but the degree of the transactivation by p51/p63 differed from that by p53. These results suggest that the cellular signal on p51/p63 cross-talks partially but not completely with that of the p53 pathway.
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PMID:The transcriptional activities of p53 and its homologue p51/p63: similarities and differences. 1038 30

Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Here we report that hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. Pretreatment of cells with an inhibitor of histone deacetylases that relieves transcriptional repression resulted in a significant reduction of p53-dependent transrepression and hypoxia-induced apoptosis. These results led us to propose a model in which different cellular pools of p53 can modulate transcriptional activity through interactions with transcriptional coactivators or corepressors. Genotoxic stress induces both kinds of interactions, whereas stresses that lack a DNA damage component as exemplified by hypoxia primarily induce interaction with corepressors. However, inhibition of either type of interaction can result in diminished apoptotic activity.
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PMID:Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation. 1115 15

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1alpha and HIF-1beta subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1alpha expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1alpha for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1alpha. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1alpha expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1alpha protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1alpha but instead stimulates HIF-1alpha synthesis in a rapamycin-dependent manner. The 5'-untranslated region of HIF-1alpha mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1alpha expression.
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PMID:HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. 1135 7

p53 is a transcriptional activator which has been implicated as a key regulator of neuronal cell death after acute injury. We have shown previously that p53-mediated neuronal cell death involves a Bax-dependent activation of caspase 3; however, the transcriptional targets involved in the regulation of this process have not been identified. In the present study, we demonstrate that p53 directly upregulates Apaf1 transcription as a critical step in the induction of neuronal cell death. Using DNA microarray analysis of total RNA isolated from neurons undergoing p53-induced apoptosis a 5-6-fold upregulation of Apaf1 mRNA was detected. Induction of neuronal cell death by camptothecin, a DNA-damaging agent that functions through a p53-dependent mechanism, resulted in increased Apaf1 mRNA in p53-positive, but not p53-deficient neurons. In both in vitro and in vivo neuronal cell death processes of p53-induced cell death, Apaf1 protein levels were increased. We addressed whether p53 directly regulates Apaf1 transcription via the two p53 consensus binding sites in the Apaf1 promoter. Electrophoretic mobility shift assays demonstrated p53-DNA binding activity at both p53 consensus binding sequences in extracts obtained from neurons undergoing p53-induced cell death, but not in healthy control cultures or when p53 or the p53 binding sites were inactivated by mutation. In transient transfections in a neuronal cell line with p53 and Apaf1 promoter-luciferase constructs, p53 directly activated the Apaf1 promoter via both p53 sites. The importance of Apaf1 as a p53 target gene in neuronal cell death was evaluated by examining p53-induced apoptotic pathways in primary cultures of Apaf1-deficient neurons. Neurons treated with camptothecin were significantly protected in the absence of Apaf1 relative to those derived from wild-type littermates. Together, these results demonstrate that Apaf1 is a key transcriptional target for p53 that plays a pivotal role in the regulation of apoptosis after neuronal injury.
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PMID:APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death. 1159 30

The induction of apoptosis is a fundamental mechanism by which the p53 transcriptional activator protein suppresses tumor development. Recently, the roles of several p53 target genes in mediating the p53 apoptotic response have been queried through loss-of-function analysis with knockout mouse models. These studies have demonstrated that the p53 targets Noxa, Puma, and Perp play cell type-specific roles in p53-mediated apoptosis. Perp, a tetraspan protein localizing to the plasma membrane, rather than to mitochondria, is a novel type of p53 effector that may stimulate apoptosis through a different mechanism from the BH3-containing proteins Noxa, Puma, and Bax.
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PMID:Perp-etrating p53-dependent apoptosis. 1472 58

The p53 tumour suppressor functions as a transcriptional activator, and several p53-inducible genes that play a critical proapoptotic role have been described. Moreover, p53 regulates the expression of various proteins participating in autoregulatory feedback loops, including proteins that negatively control p53 stability (Mdm2 and Pirh2) or modulate stress-induced phosphorylation of p53 on Ser-46 (p53DINP1 or Wip1), a key event for p53-induced apoptosis. Here, we describe a new systematic analysis of p53 targets using oligonucleotide chips, and report the identification of dapk1 as a novel p53 target. We demonstrate that dapk1 mRNA levels increase in a p53-dependent manner in various cellular settings. Both human and mouse dapk1 genomic loci contain DNA sequences that bind p53 in vitro and in vivo. Since dapk1 encodes a serine/threonine kinase previously shown to suppress oncogene-induced transformation by activating a p19ARF/p53-dependent apoptotic checkpoint, our results suggest that Dapk1 participates in a new positive feedback loop controlling p53 activation and apoptosis.
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PMID:dapk1, encoding an activator of a p19ARF-p53-mediated apoptotic checkpoint, is a transcription target of p53. 1560 85

The tumor suppressor p53 functions as a transcriptional activator to induce cell cycle arrest and apoptosis in response to DNA damage. Although p53 was also shown to mediate apoptosis in a manner independent of its transactivation activity, the mechanism and conditions that trigger such cell death have remained largely unknown. We have now shown that inhibition of RNA polymerase II-mediated transcription by alpha-amanitin or RNA interference induced p53-dependent apoptosis. Inhibition of pol II-mediated transcription resulted in down-regulation of p21Cip1, which was caused by both transcriptional suppression and protein degradation, despite eliciting p53 accumulation, allowing the cells to progress into S phase and then to undergo apoptosis. This cell death did not require the transcription of p53 target genes and was preceded by translocation of the accumulated p53 to mitochondria. Our data thus suggested that blockade of pol II-mediated transcription induced p53 accumulation in mitochondria and was the critical factor for eliciting p53-dependent but transcription-independent apoptosis.
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PMID:Transcriptional blockade induces p53-dependent apoptosis associated with translocation of p53 to mitochondria. 1575 95

Mutations in the p53 tumor suppressor gene occur in more than 50% of human cancers. In response to various cellular stresses, such as DNA damage, the p53 protein rapidly accumulates by posttranscriptional mechanism(s) and activates the expression of genes that play a major role in cellular responses leading to cell cycle arrest, DNA repair and apoptosis as a transcriptional activator. In particular, the induction of apoptosis is considered to be an important function in tumor suppression by p53. Recently, two BH3-only members of the Bcl-2 family, Noxa and PUMA, have been identified as p53 target genes. Furthermore, the analysis of mice doubly deficient in multidomain Bcl-2 family proteins, Bax and Bak, revealed that apoptosis induced by the BH3-only protein is completely dependent on Bax and Bak. More recently, it was demonstrated using gene knockout mice that Noxa and PUMA function as the effectors of p53-induced apoptosis. These analyses revealed that p53-induced apoptosis is regulated by these Bcl-2 family proteins. In this photogravure, the regulation of these Bcl-2 family proteins in p53-induced apoptosis was visualized by fluorescent protein fusion and immune fluorescence methods.
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PMID:Involvement of Bcl-2 family proteins in p53-induced apoptosis. 1611 88


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