Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumor suppressor protein plays a central role in maintaining genomic integrity. It does so by occupying a nodal point in the DNA damage control pathway. When cells are subject to ionizing radiation or other mutagenic events, p53 mediates cell cycle arrest or programmed cell death (apoptosis). Furthermore, some evidence suggests that p53 plays a role in the recognition and repair of damaged DNA. Biochemically, p53 is a sequence-specific transcriptional stimulator and a non-specific transcriptional repressor but also engages in multiple protein-protein interactions. Conversely, disruption of the p53 response pathway strongly correlates with tumorigenesis. p53 is functionally inactivated by structural mutations, neutralization by viral products, and non-mutational cellular mechanisms in the majority of human cancers. p53-deficient mice have a highly penetrant tumor phenotype, with over 90% tumor incidence within nine months. In some cancers, direct physical evidence exists identifying the p53 gene as a target of known environmental carcinogens such as UV light and benzolalpyrene in cancers of the skin and lung. When p53 loss occurs, cells do not get repaired or eliminated but rather proceed to replicate damaged DNA, which results in more random mutations, gene amplifications, chromosomal re-arrangements, and aneuploidy. In some experimental models, loss of p53 confers resistance to anticancer therapy due to loss of apoptotic competence. The translational potential of these discoveries is beginning to be tested in novel p53-based therapies.
 ...
PMID:p53--an acrobat in tumorigenesis. 948 46

Leukemic lymphoblasts expressing the E2A-HLF oncoprotein possess wild-type p53 genes, but do not undergo apoptosis in response to DNA damage. Experimentally, E2A-HLF prevents apoptosis due to growth factor deprivation or gamma-irradiation in interleukin-3 (IL-3)-dependent murine pro-B cells. To directly test the chimeric protein's ability to abrogate p53-mediated cell death, we used mouse myeloid leukemia cells (M1p53tsval) that constitutively express a temperature-sensitive (ts) mutant p53 gene and undergo apoptosis when p53 assumes an active wild-type configuration. This effect is blocked by treatment with IL-6, which allows the cells to survive in culture despite wild-type p53 activation. We introduced E2A-HLF into M1p53tsval cells and found that they were resistant to p53-mediated apoptosis and that E2A-HLF effectively substituted for the survival functions of IL-6. The expression of p53-responsive genes such as p21 and Bax was upregulated normally, suggesting that E2A-HLF acts downstream of p53 to block execution of the p53-induced apoptotic program. NFIL3, a growth factor-regulated bZIP protein that binds to the same DNA-consensus site as E2A-HLF, delays apoptosis in IL-3-dependent pro-B cells deprived of growth factor. By contrast, in the present study, enforced expression of NFIL3 failed to protect M1p53tsval cells from p53-dependent apoptosis and actively antagonized the ability of IL-6 to rescue cells from that fate, consistent with its role as either a transcriptional repressor or activator, depending on the cell type in which it is expressed. We conclude that the E2A-HLF chimera abrogates p53-induced apoptosis in leukemic cells, possibly through the transcriptional modulation of cell death pathways that are activated by p53 in response to DNA damage.
 ...
PMID:The chimeric E2A-HLF transcription factor abrogates p53-induced apoptosis in myeloid leukemia cells. 969 29

The mdm2 gene is positively regulated by p53 through a p53-responsive DNA element in the first intron of the mdm2 gene. mdm2 binds p53, thereby abrogating the ability of p53 to activate the mdm2 gene, and thus forming an autoregulatory loop of mdm2 gene regulation. Although the mdm2 gene is thought to act as an oncogene by blocking the activity of p53, recent studies indicate that mdm2 can act independently of p53 and block the G1 cell cycle arrest mediated by members of the retinoblastoma gene family and can activate E2F1/DP1 and the cyclin A gene promoter. In addition, factors other than p53 have recently been shown to regulate the mdm2 gene. In this article, we report that thyroid hormone (T3) receptors (T3Rs), but not the closely related members of the nuclear thyroid hormone/retinoid receptor gene family (retinoic acid receptor, vitamin D receptor, peroxisome proliferation activation receptor, or retinoid X receptor), regulate mdm2 through the same intron sequences that are modulated by p53. Chicken ovalbumin upstream promoter transcription factor I, an orphan nuclear receptor which normally acts as a transcriptional repressor, also activates mdm2 through the same intron region of the mdm2 gene. Two T3R-responsive DNA elements were identified and further mapped to sequences within each of the p53 binding sites of the mdm2 intron. A 10-amino-acid sequence in the N-terminal region of T3Ralpha that is important for transactivation and interaction with TFIIB was also found to be important for activation of the mdm2 gene response element. T3 was found to stimulate the endogenous mdm2 gene in GH4C1 cells. These cells are known to express T3Rs, and T3 is known to stimulate replication of these cells via an effect in the G1 phase of the cell cycle. Our findings, which indicate that T3Rs can regulate the mdm2 gene independently of p53, provide an explanation for certain known effects of T3 and T3Rs on cell proliferation. In addition, these findings provide further evidence for p53-independent regulation of mdm2 which could lead to the development of tumors from cells that express low levels of p53 or that express p53 mutants defective in binding to and activating the mdm2 gene.
 ...
PMID:Regulation of the mdm2 oncogene by thyroid hormone receptor. 985 9

Control of cell growth and division by the p53 tumor suppressor protein requires its abilities to transactivate and repress specific target genes and to associate in complex with other proteins. Here we demonstrate that p53 binds to the E1A-regulated transcription factor p120E4F, a transcriptional repressor of the adenovirus E4 promoter. The interaction involves carboxy-terminal half of p120E4F and sequences located at the end of the sequence-specific DNA-binding domain of p53. Ectopic expression of p120E4F leads to a block of cell proliferation in several human and murine cell lines and this effect requires the association with wild-type (wt) p53. Although p120E4F can also bind to mutant p53, the growth suppression induced by overexpression of the protein is severely reduced in a cell line that contains mutant p53. These data suggest that p120E4F may represent an important element within the complex network of p53 checkpoint functions.
 ...
PMID:p53 is involved in the p120E4F-mediated growth arrest. 1064 96

The tumor suppressor protein p53 is a transcription factor that can positively regulate the expression of critical target genes involved in negative control of cell growth or induction of apoptosis; p53 is also able to suppress the transcription of other genes by virtue of its ability to bind components of the basal transcription machinery. Over 50% of human tumors are characterized by p53 mutations that result in a loss of wild-type p53 (wtp53) function in the transcriptional control of these target genes. We have exploited this loss of p53 function in the regulation of gene transcription to develop a novel gene therapy strategy that maximizes expression of the potential therapeutic gene in tumors while simultaneously down-regulating the same gene in normal cells. In one construct (unit I), the potential therapeutic gene (in this case represented by a luciferase reporter) is placed under the control of a promoter such as the heat shock protein 70 gene promoter, which is repressed by wtp53 but overexpressed in many tumor cells with defective p53 function. Residual expression of the reporter in normal cells is repressed by cotransfection of another construct (unit II) consisting of a repressor of unit I under the control of a promoter that is activated by wtp53 expression. Unit II contains a promoter with a consensus wtp53 binding site driving a transcriptional repressor or an antisense construct for the gene in unit I. Our results suggest that this dual control approach may represent a strategy with wide applications in the field of cancer gene therapy.
 ...
PMID:Targeting gene expression to tumor cells with loss of wild-type p53 function. 1067 50

HIC-1 (hypermethylated in cancer 1), a BTB/POZ transcriptional repressor, was isolated as a candidate tumor suppressor gene located at 17p13.3, a region hypermethylated or subject to allelic loss in many human cancers and in the Miller-Dieker syndrome. The human HIC-1 gene is composed of two exons, a short 5'-untranslated exon and a large second coding exon. Recently, two murine HIC-1 isoforms generated by alternative splicing have been described. To determine whether such isoforms also exist in human, we have further analyzed the human HIC-1 locus. Here, we describe and extensively characterize a novel alternative noncoding upstream exon, exon 1b, associated with a major GC-rich promoter. We demonstrate using functional assays that the murine exon 1b previously described as coding from computer analyses of genomic sequences is in fact a noncoding exon highly homologous to its human counterpart. In addition, we report that the human untranslated exon is presumably a coding exon, renamed exon 1a, both in mice and humans. Both types of transcripts are detected in various normal human tissues with a predominance for exon 1b containing transcripts and are up-regulated by TP53, confirming that HIC-1 is a TP53 target gene. Thus, HIC-1 function in the cell is controlled by a complex interplay of transcriptional and translational regulation, which could be differently affected in many human cancers.
 ...
PMID:Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53. 1107 60

Interferons are important in regulating cell growth and differentiation, immune function and initiating anti-viral responses. While the pleotrophic actions of interferons have been well documented, the molecular mechanisms underpinning their biological effects have not been fully characterized. IFI 16 is a member of the interferon-inducible HIN-200 family of nuclear proteins, which we have recently shown can function as a potent transcriptional repressor. A murine member of the HIN-200 family, p202, can indirectly interact with p53 via the p53 binding protein (p53bp) and inhibit p53-mediated transcriptional activation. The binding activity of p202 to p53bp was shown to require the conserved MFHATVAT motif present in all 200 amino acid repeat regions of HIN-200 proteins. Given that IFI 16 contains two MFHATVAT motifs, we sought to determine whether IFI 16 may form a complex with p53 and if so to ascertain the functional significance of this interaction. We demonstrate that IFI 16 can directly bind to the C-terminal region of p53 and augment p53-mediated transcriptional activation without altering the steady state levels of p53. Thus, in addition to its ability to directly regulate gene expression, IFI 16 can also modulate the transcription function of other cellular transcription factors. These findings demonstrate a possible link between gene induction following interferon stimulation and p53-mediated cellular events.
 ...
PMID:Functional interaction between p53 and the interferon-inducible nucleoprotein IFI 16. 1114 55

The zinc finger protein RE-1 silencing transcription factor (REST) is a transcriptional repressor that represses neuronal genes in non-neuronal tissues. We have analyzed the ability of REST and the REST mutants, RESTDeltaN and RESTDeltaC lacking either the N-terminal or C-terminal repression domains of REST, to inhibit transcription mediated by distinct transcriptional activator proteins. For this purpose we have designed an activator specific assay where transcription is activated as a result of only one distinct activation domain. In addition, binding sites for REST were inserted in the 5'-untranslated region or at a distant position downstream of the polyadenylation signal. The results show that REST or the REST mutants containing only one repression domain were able to block transcriptional activation mediated by the transcriptional activation domains derived from p53, AP2, Egr-1, and GAL4. Moreover, REST, as well as the REST mutants, blocked the activity of the phosphorylation-dependent activation domain of Elk1. However, the activity of the activation domain derived from cAMP response element binding protein 2 (CREB2), was not inhibited by REST, RESTDeltaN or RESTDeltaC, suggesting that REST is able to distinguish between distinct transcriptional activation domains. Additionally, the activator specific assay, together with a positive-dominant mutant of REST that activated instead of repressed transcription, was used in titration experiments to show that REST has transcriptional repression and no transcriptional activation properties when bound to the 5'-untranslated region of a gene.
 ...
PMID:Biological activity of RE-1 silencing transcription factor (REST) towards distinct transcriptional activators. 1170 59

The newly discovered p73 gene encodes a nuclear protein that has high homology with p53. Furthermore, ectopic expression of p73 in p53(+/+) and p53(-/-) cancer cells recapitulates some of the biological activities of p53 such as growth arrest, apoptosis, and differentiation. p73(-/-)-deficient mice exhibit severe defects in proper development of the central nervous system and pheromone sensory pathway. They also suffer from inflammation and infections. Here we studied the transcriptional regulation of p73 at the crossroad between proliferation and differentiation. p73 mRNA is undetectable in proliferating C2C12 cells and is expressed at very low levels in undifferentiated P19 and HL60 cells. Conversely, it is upregulated during muscle and neuronal differentiation as well as in response to tetradecanoyl phorbol acetate-induced monocytic differentiation of HL60 cells. We identified a 1-kb regulatory fragment located within the first intron of p73, which is positioned immediately upstream to the ATG codon of the second exon. This fragment exerts silencer activity on p73 as well as on heterologous promoters. The p73 intronic fragment contains six consensus binding sites for transcriptional repressor ZEB, which binds these sites in vitro and in vivo. Ectopic expression of dominant-negative ZEB (ZEB-DB) restores p73 expression in proliferating C2C12 and P19 cells. Thus, transcriptional repression of p73 expression by ZEB binding may contribute to the modulation of p73 expression during differentiation.
 ...
PMID:The transcriptional repressor ZEB regulates p73 expression at the crossroad between proliferation and differentiation. 1171 81

Deregulation of the retinoblastoma protein (pRB) pathway is a hallmark of cancer. In the absence of other genetic alterations, this deregulation results in lack of differentiation, hyperproliferation and apoptosis. The pRB protein acts as a transcriptional repressor by targeting the E2F transcription factors, whose functions are required for entry into S phase. Increased E2F activity can induce S phase in quiescent cells--this is a central element of most models for the development of cancer. We show that although E2F1 alone is not sufficient to induce S phase in diploid mouse and human fibroblasts, increased E2F1 activity can result in S-phase entry in diploid fibroblasts in which the p53-mediated G1 checkpoint is suppressed. In addition, we show that E2F1 can induce S phase in primary mouse fibroblasts lacking pRB. These results indicate that, in addition to acting as an E2F-dependent transcriptional repressor, pRB is also required for the cells to retain the G1 checkpoint in response to unprogrammed proliferative signals.
 ...
PMID:Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry. 1199 23


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>