Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Mutations in the core domain of the tumour suppressor p53 gene occur in over 50% of human cancers and are not present in normal cells hence p53 protein is a prime target for anti-cancer therapy. In full-length p53 protein, mutations have been shown to destabilize protein structure from wild-type to mutant conformation resulting in differential exposure of conformational epitopes PAb1620, PAb240 and PAb246 in murine p53 protein. In recent studies, putative anti-cancer agents have been designed for rescuing wild-type p53 conformation and function. Using full-length and truncated murine p53 proteins derived from the baculoviral system, we analyzed the recovery of PAb246 and PAb1620 epitopes and have identified regions of p53 required for optimal renaturation in vitro to wild-type. The influence of ATP and ADP on the process was also determined. We demonstrate a difference in the dose-dependent effect of ATP and ADP on renaturation of full-length wild-type and monomeric p53 proteins. Putative ATP binding sites were identified at residues 1-67 and 98-303 in conjunction with a putative ADP binding site at residues 98-303 and negative regulation of ATP/ADP binding by the proline-rich region. Improved efficacy and reduced toxicity of anti-cancer therapy may depend upon compounds engineered to rescue hot-spot core mutations in the context of full-length p53.
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PMID:Restoration of wild-type conformation to full-length and truncated p53 proteins: specific effects of ATP and ADP. 1532 74

Microtubule-damaging agents (MDA) are potent antineoplastic drugs that are widely used in clinical treatment for a variety of cancers. However, the precise mechanisms underlying MDA-induced cell death are largely unknown. Here, we report that both p53 and Bax are central participants in the MDA-mediated cell death machinery in HCT116 human colon cancer cells. MDA, including epothilone B analogue (BMS-247550) and vinblastine, induced apoptosis of Bax-positive HCT116 cells in a p53-dependent manner; p53 was required for MDA-induced Bax conformational change. In response to MDA treatment, the BH3-only proapoptotic protein PUMA was up-regulated in p53-positive but not in p53 knockout HCT116 cells. Moreover, PUMA knockout HCT116 cells were resistant to MDA-induced Bax conformational change and apoptosis. In addition, introducing p53 plasmid DNA into p53-deficient HCT116 cells restored PUMA expression and apoptotic response to MDA treatment. However, ectopic expression of the p53 point mutation L22Q/W23S, but not the proline-rich domain deletion mutants 83-393 and DeltaProAE, could also sensitize p53 knockout HCT116 cells to MDA-induced Bax activation and apoptosis, although all mutants failed to restore PUMA expression. Together, these findings suggest that p53 acts upstream of Bax to promote MDA-mediated cell death in a proline-rich domain-dependent manner through both transcription-dependent (by up-regulating PUMA expression) and -independent mechanisms in human colon cancer HCT116 cells.
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PMID:Regulation of Bax activation and apoptotic response to microtubule-damaging agents by p53 transcription-dependent and -independent pathways. 1526 86

Etk/Bmx, a member of the Tec family of nonreceptor tyrosine kinases, has been implicated in the regulation of various cellular processes including proliferation, differentiation, motility, and apoptosis. Here, we report the identification of Tec family kinases as the potential interacting proteins of the tumor suppressor p53 by an Src homology 3 domain array screening. Etk is physically associated with p53 through its Src homology 3 domain and the proline-rich domain of p53. Induction of p53 expression by DNA damage inhibits Etk activity in several cell types. Down-regulation of Etk expression by a specific small interfering RNA sensitizes prostate cancer cells to doxorubicin-induced apoptosis, suggesting that inhibition of Etk activity is required for apoptosis in response to DNA damage. We also show that Etk primarily interacts with p53 in the cytoplasm and that such interaction leads to bidirectional inhibition of the activities of both proteins. Overexpression of Etk in prostate cancer cells results in inhibition of p53 transcriptional activity and its interaction with the mitochondrial protein BAK and confers the resistance to doxorubicin. Therefore, we propose that the stoichiometry between p53 and the Tec family kinases in a given cell type may determine its sensitivity to chemotherapeutic drugs.
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PMID:Bi-directional regulation between tyrosine kinase Etk/BMX and tumor suppressor p53 in response to DNA damage. 1535 90

Inactivation of p53 and activation of telomerase occur in the majority of human cancers, raising the possibility of a link between these two pathways. Overexpression of wild-type p53 down-regulates the enzymatic activity of telomerase in various cancer cell lines through transcriptional repression of its catalytic subunit, human telomerase reverse transcriptase (hTERT). In this study, we re-evaluated the role of p53 in telomerase regulation using isogenic cell lines expressing physiological levels of p53. We demonstrate that endogenous wild-type p53 was able to down-regulate telomerase activity, hTERT mRNA levels, and promoter activity; however, the ability to repress hTERT expression was found to be cell type-specific. The integrity of the DNA-binding core domain, the N-terminal transactivation domain, and the C-terminal oligomerization domains of p53 was essential for hTERT promoter repression, whereas the proline-rich domain and the extreme C terminus were not required. Southwestern and chromatin immunoprecipitation experiments demonstrated lack of p53 binding to the hTERT promoter, raising the possibility of an indirect repressive mechanism. The down-regulation of hTERT promoter activity was abolished by a dominant-negative E2F1 mutant. Mutational analysis identified a specific E2F site responsible for p53-mediated repression. Knockdown of the key p53 transcriptional target, p21, was sufficient to eliminate the p53-dependent repression of hTERT. Inactivation of the Rb family using either viral oncoproteins or RNA interference attenuated the repression. Inhibition of histone deacetylases also interfered with the repression of hTERT by p53. Therefore, our results suggest that repression of hTERT by endogenous p53 is mediated by p21 and E2F.
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PMID:p53-dependent down-regulation of telomerase is mediated by p21waf1. 1537 22

The protein kinase Prk1p (standing for p53 regulating kinase 1) of the yeast Saccharomyces cerevisiae is the prototype of a kinase family identified recently as important regulators of the actin cytoskeleton and endocytosis. These kinases all have a highly homologous serine/threonine kinase domain in their N-terminal region but share no significant homology in other regions. Prk1p also contains a proline-rich motif near its C-terminus that is required for the proper subcellular localization of the protein. The kinase activity of Prk1p has been confirmed by both in vitro and in vivo studies and shown to be essential for the protein's function. To date, several proteins that play essential roles in actin cytoskeleton organization and endocytosis have been identified as the regulatory targets of Prk1p. Phosphorylation on the [L/I/V/N]xx[Q/N/T/S]xTG motifs by Prk1p results in a down-regulation of the functions of these target proteins. The observation that many yeast proteins involved in the actin cytoskeleton organization and endocytosis contain the Prk1p phosphorylation motifs has led to the hypothesis that the Prk1p family of kinases are possibly the general regulators of the actin cytoskeleton and endocytosis in yeast.
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PMID:Prk1p. 1538 Nov 49

Reactivation in Epstein-Barr virus (EBV) is closely associated with a G(0)/G(1) cell cycle arrest which can be induced either by lytic cycle-inducing agents or by the immediate-early gene product Zta. Accumulating evidence shows that in epithelial cells, downregulation of the proto-oncogene, c-myc, plays an important role in lytic cycle-associated cell growth arrest. Here, we provide evidence that c-Myc provides a gatekeeper function to ensure that certain cell cycle inhibitory events have been capitulated prior to full progression into the lytic cycle. Specifically, we show that reconstitution of c-Myc expression during the lytic cycle to levels observed in cycling uninduced cells inhibits the transactivation function of Zta. Nuclear localization studies show that c-Myc does not grossly alter the nuclear localization of Zta or its association with the insoluble nuclear fraction. Enforced expression of another transcription factor that promotes cell cycle progression, E2F1, also inhibits Zta transactivation. Analysis of c-Myc- and E2F1-mediated inhibition of a panel of Zta mutants shows parallel genetics and inhibition maps to a small bipartite sequence located between amino acids 29 and 53 of Zta, containing homology to the proline-rich domain of the tumor suppressor protein p53. Mutation of a conserved tryptophan residue located at amino acid 49 of Zta largely prevents inhibition by both c-Myc and E2F1. These studies identify a negative regulatory element within the Zta activation domain that is regulated by the cell cycle-promoting factors c-Myc and E2F1.
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PMID:Identification of a negative regulatory element in the Epstein-Barr virus Zta transactivation domain that is regulated by the cell cycle control factors c-Myc and E2F1. 1547 36

The WWOX gene encodes a tumor suppressor WW domain-containing protein, Wwox. Alterations of WWOX have been demonstrated in multiple types of cancer, and introduction of Wwox into Wwox-negative tumor cells has resulted in tumor suppression and apoptosis. The Wwox protein contains two WW domains that typically bind proline-rich motifs and mediate protein-protein interactions. Recently, we have described functional cross-talk between the Wwox protein and the p53 homologue, p73. To further explore the biological function of Wwox, we investigated other interacting candidates. In this report, we demonstrate a physical and functional association between AP-2gamma transcription factor and the Wwox protein. AP-2gamma at 20q13.2 encodes a transcription factor and is frequently amplified in breast carcinoma. We show that Wwox binds to the PPPY motif of AP-2gamma via its first WW domain. Alterations of tyrosine 33 in the first WW domain of Wwox or the proline-rich motif in AP-2gamma dramatically reduce this interaction. In addition, our results demonstrate that Wwox expression triggers redistribution of nuclear AP-2gamma to the cytoplasm, hence suppressing its transactivating function. Our results suggest that Wwox tumor suppressor protein inhibits AP-2gamma oncogenic activity by sequestering it in the cytoplasm.
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PMID:Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor. 1554 92

Necdin is a growth suppressor expressed predominantly in postmitotic neurons. The necdin gene is involved in the etiology of the genomic imprinting-associated neurodevelopmental disorder Prader-Willi syndrome and belongs to the MAGE gene family. All the MAGE family proteins contain a large homology domain termed the MAGE homology domain (MHD). We here characterize the regions of necdin required for the protein-protein interaction, nuclear matrix targeting, and cell growth suppression. The region including entire MHD (amino acids 116-280) of necdin was required for its interaction with p53, while the regions amino acids 144-184 and 191-222 within the MHD were required for both the nuclear matrix targeting and the cell growth suppression of osteosarcoma SAOS-2 cells. The amino-terminal proline-rich acidic region (amino acids 60-100) was also necessary for cell growth suppression. Tetracycline-regulatable overexpression of necdin induced growth arrest of SAOS-2 cells in a reversible manner, and the necdin-overexpressing cells showed a large, flattened morphology with double nuclei. In contrast, a necdin mutant lacking amino acids 191-222 did not induce such changes. These findings suggest that different functions of necdin are mediated via its distinct domains.
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PMID:Functional domains of necdin for protein-protein interaction, nuclear matrix targeting, and cell growth suppression. 1557 80

The p53 protein can adopt several conformations in cells--"latent," "active," or mutant--depending on cellular stress or mutations of the TP53 gene. Today, only a few antibodies discriminating these conformations are available. We produced three new anti-p53 monoclonal antibodies (MAbs) directed against epitopes of human p53. The H53C1 MAb recognizes an epitope located at the N-terminal part of the central region of p53 and can discriminate mutant from wild-type conformation. The H53C2 and H53C3 MAbs are against different epitopes within the proline-rich region of p53. Moreover, the H53C2 epitope is located in the second negative regulatory domain of p53 between residues 80 and 93. These MAbs can be used as new tools to study and modulate the cellular functions of p53.
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PMID:A new set of monoclonal antibodies directed to proline-rich and central regions of p53. 1567 6

The function of p73, a transcription factor belonging to the p53 family, is finely regulated by its steady-state protein stability. p73 protein degradation/stabilization can be regulated by mechanisms in part dependent on the ubiquitin proteasome system (UPS): (i) Itch/NEDD4-like UPS degradation, (ii) NEDD8 UPS degradation, and (iii) NQO1 20S proteasome-dependent (but ubiquitin-independent) breakdown. Here, we show that, in vitro, Calpain I can cleave p73 at two distinct sites: the first proline-rich region and within the oligomerization domain. Consequently, different p73 isoforms can be degraded by calpains, i.e., both N-terminal isoforms (TAp73 and DeltaNp73) as well as the C-terminal isoforms (alpha, beta, gamma, delta). Moreover, overexpression of the specific endogenous calpain inhibitor, calpastatin, in cultured cells increased the steady-state p73 level. This suggests that calpains may play a physiological role in the regulation of p73 protein stability.
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PMID:Calpain cleavage regulates the protein stability of p73. 1597 58


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