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)

Molecular analysis of hereditary nonpolyposis colorectal carcinomas (HNPCC) has identified DNA mismatch repair deficiencies with resulting microsatellite instability (MSI) as a pathway of carcinogenesis that appears to be relevant for prognosis, treatment, and possibly prevention. In this study, expression of cell cycle proteins and other known prognostic markers is correlated with the microsatellite status of colorectal cancers (CRC). One hundred consecutive cases from the CRC Registry at Thomas Jefferson University were analyzed for MSI. Immunohistochemistry was performed for the mismatch repair proteins hMLH1 and hMSH2, tumor suppressor p53, apoptosis inhibitor bcl-2, cell cycle proteins p21(WAF1/CIP1), and p27 and the proliferation markers Ki-67 and topoisomerase II. High MSI (MSI-H) is significantly correlated with loss of either hMLH1 or hMSH2, presence of bcl-2, and absence of p53. p21(WAF1/CIP1) is positive in all tumors with MSI-H. Previous findings of a lower proliferation rate were confirmed with a topoisomerase II stain. Microsatellite stable (MSS) tumors generally express both MSH2 and MLH1. Other highly significant differences are positive p53 in 56% of MSS cases and negative bcl-2 in 98% of MSS cases. p27 expression is found in approximately 50% of all CRCs irrespective of the microsatellite status. MSI-H tumors follow the mutator pathway, with loss of expression of one mismatch repair protein, wild-type p53, lower proliferation, and positivity for p21(WAF1/CIP1). MSS tumors follow the suppressor pathway, characterized by p53 overexpression, higher proliferation, and absence of bcl-2 expression; p21(WAF1/CIP1) expression can be variable. These data provide a molecular basis for the clinical observation that patients with HNPCC appear to have a more favorable prognosis. HUM PATHOL 31:1506-1514.
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PMID:Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers. 1115 Mar 76

The cytoplasmic adaptor protein FADD is an essential component of the death-inducing signaling complexes (DISCs) that assemble when TNF receptor family members, such as Fas, are ligated. FADD inititates the proteolytic cascade that leads to apoptosis by binding to and promoting the autocatalytic activation of caspase-8 [1-4]. Surprisingly, FADD (but not caspase-8) is also required for T cells to proliferate upon their stimulation with mitogens [5-9]. Using transgenic mice expressing a dominant-negative mutant of FADD (FADD-DN), we show that functional FADD is required for T cells to proliferate in response to antigens in vivo as well as to mitogens in culture. The costimulation of wild-type and FADD-DN T cells with mitogens revealed that FADD-DN T cells have a cell-autonomous defect in intracellular signaling. In contrast to another study [6], p53 deficiency did not rescue mitogen-induced proliferation of FADD-DN T cells, and neither did enforced expression of the apoptosis inhibitor Bcl-2. Like wild-type T cells, FADD-DN T cells stimulated with mitogens mobilized intracellular calcium and activated members of the NF-kappaB transcription factor family as well as p38 mitogen-activated protein kinase (MAPK) and p44/42 MAPK. Therefore, FADD must act downstream of or in parallel to these signaling pathways.
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PMID:Effects of a dominant interfering mutant of FADD on signal transduction in activated T cells. 1125 Jan 57

Survivin is a member of the inhibitor of apoptosis family. This apoptosis inhibitor also has an evolutionarily conserved role as a mitotic spindle checkpoint protein. Previous studies on p53-repressed genes have implicated several genes involved in the G(2)/M transition of the cell cycle as targets of negative regulation by p53. However, few targets of p53 repression that are anti-apoptotic have been identified. This study identifies the anti-apoptotic survivin gene as a p53-repressed gene. Notably, Survivin repression by p53 is shown to be distinct from p53-dependent growth arrest. Chromatin immunoprecipitations indicate that p53 binds the survivin promoter in vivo; immunobinding studies indicate that this site overlaps with a binding site for E2F transcription factors and is subtly distinct from a canonical p53-transactivating element. The survivin-binding site contains a 3-nucleotide spacer between the two decamer "half-sites" of the p53 consensus element; deletion of this spacer is sufficient to convert the survivin site into a transactivating element. Finally, we show that overexpression of Survivin in cells sensitive to p53-dependent cell death markedly inhibits apoptosis induced by ultraviolet light. The identification of survivin as a p53 repressed gene should aid in the elucidation of the contribution of transcriptional repression to p53-dependent apoptosis.
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PMID:Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. 1171

A checkpoint surveying the entry into mitosis responds to defects in spindle microtubule assembly/stability. This has been used to trigger apoptosis in cancer cells, but how the spindle checkpoint couples to the cell survival machinery has remained elusive. Here, we report that microtubule stabilization engenders a survival pathway that depends on elevated activity of p34(cdc2) kinase and increased expression of the apoptosis inhibitor and mitotic regulator, survivin. Pharmacologic, genetic, or molecular ablation of p34(cdc2) kinase after microtubule stabilization resulted in massive apoptosis independent of p53, suppression of tumor growth, and indefinite survival without toxicity in mice. By ablating this survival checkpoint, inhibitors of p34(cdc2) kinase could safely improve the efficacy of microtubule-stabilizing agents used to treat common cancers.
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PMID:A p34(cdc2) survival checkpoint in cancer. 1215 Aug 24

Aberrant expression of the apoptosis inhibitor bcl-2 provides a survival advantage throughout oncogenesis and can facilitate chemotherapeutic resistance in a variety of human cancers. Follicular lymphoma (FL) for example, is characterized by the chromosomal translocation t(14;18), which results in bcl-2 overexpression and initiates lymphomagenesis. Although FL cells possess ample amounts of bcl-2, they respond remarkably well to standard first-round chemotherapy. However, the vast majority of patients relapses and becomes progressively resistant to therapy. We obtained cell lines derived from chemosensitive and chemoresistant FL patients, that are characterized by the chromosomal translocation t(14;18) and expression of bcl-2, to investigate how chemotherapeutic drugs can circumvent bcl-2 anti-apoptotic function and to identify alterations in those pathways that may facilitate resistance to DNA damaging drugs. In chemosensitive FL cells, we found that DNA damaging drugs promote apoptosis through p53-dependent upregulation of the TRAIL-DR5 receptor, resulting in activation of caspase-8 and downstream executioner caspases, thereby evading bcl-2 mediated suppression of apoptosis. Examination of drug resistant FL cell lines revealed that at least two defects in this pathway can contribute to chemotherapeutic resistance: 1. p53 gene mutations that disable the transcriptional response to DNA damaging drugs, including expression of the TRAIL-DR5 receptor, and 2. transcriptional repression of the cell-death executioner enzyme caspase-3.
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PMID:Activation and suppression of the TRAIL death-receptor pathway in chemotherapy sensitive and resistant follicular lymphoma cells. 1461 23

The adenovirus E1B-55-kDa protein binds and inactivates the tumor suppressor protein p53. However, the role of this interaction during infection is still poorly understood and was therefore examined here. Infection with a virus carrying the E1B-55-kDa mutation R239A, preventing the interaction with p53, led to the accumulation of p53. However, p53 target genes were not activated in the infected cells, although p53 phosphorylation did occur and the p53 antagonists Mdm2 and deltaNp73 did not accumulate. Deletion of E4orf6, alone or in combination with E1B-55-kDa, did not allow the induction of p53-responsive genes either. In transient reporter assays, the viral E1A-13S protein antagonized p53 activity; mutational analysis suggested that this depends partially on p300 binding, but it depends even more strongly on the interaction of E1A with the p400/TRRAP protein complex. However, viruses expressing E1A mutants lacking these binding activities, in combination with E1B-55-kDa R239A, still abolished p53 activity. In contrast, when the mutation of E1B-55-kDa at R239A was combined with a deletion of the apoptosis inhibitor E1B-19-kDa, infected cells showed more extensive apoptosis than after infection with single mutants, suggesting that accumulated p53, albeit transcriptionally inactive, might nonetheless enhance apoptosis. Despite extensive apoptosis of the infected cells, the deletion of E1B-19-kDa, in combination with the E1B-55-kDa mutation or in the presence of the constitutively active p53 mutant p53mt24-28, reduced virus replication less than fivefold. In conclusion, adenovirus does not need direct binding of E1B-55-kDa to inactivate p53, and forced p53 activity with consecutive apoptosis does not severely impair virus replication.
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PMID:E1B-55-kilodalton protein is not required to block p53-induced transcription during adenovirus infection. 1522 Apr 43

The mechanism by which a single mutant cell clonally expands is usually assumed to involve an additional mutation in a cell cycle regulatory gene. An alternative mechanism for driving clonal expansion is apoptosis, which might create vacant stem cell compartments that can be repopulated by mutant cells. This model predicts that in a mouse with reduced apoptotic capacity (i) more mutated cells will appear initially but (ii) these cells will expand into clones more slowly than in wild-type animals. To test this hypothesis for ultraviolet B (UVB)-induced skin carcinogenesis, we examined UVB-induced p53 mutant clones and tumors in a transgenic (Tg) mouse (K14-Survivin) with skin-specific expression of the apoptosis inhibitor Survivin. To limit the effects of Survivin on apoptosis, without affecting epidermal proliferation or differentiation, we used Survivin expression levels and UVB doses that resulted in a 2-fold reduction in keratinocyte apoptosis. After 5 weeks of chronic UVB irradiation, newly created p53 mutant keratinocyte clones (indicative of initial mutation frequency) were 1.4-fold more frequent in K14-Survivin mice (P = 4 x 10(-6)). As predicted, this effect was reversed for clones growing by clonal expansion, which were rarer in Tg skin by 1.7-fold (P = 0.047). At 10 weeks large expanding Tg clones were rarer by a magnitude approaching the apoptosis differential (approximately 2-fold, P = 4 x 10(-5)). Survivin expression also retarded clonal expansion at later stages of tumor development. By 20 weeks 95% of animals carried tumors (primarily papillomas), which were 1.6-fold rarer in apoptosis-defective Tg mice (P = 0.03). In contrast, the rate of tumors attaining large size (> or =3 mm, P = 0.048) and converting to carcinoma was increased approximately 2-fold in Tg mice. Thus, Survivin-regulated apoptosis appears to suppress two stages that involve new mutations, initiation and malignant conversion, yet drives clonal expansion of existing p53 mutant cells.
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PMID:UVB-induced apoptosis drives clonal expansion during skin tumor development. 1549 93

In a previous study, we observed that cytokine-induced apoptosis inhibitor 1 (CIAPIN1), a newly identified apoptosis inhibitor, was upregulated at the mRNA level in a multidrug-resistant gastric cancer cell line SGC7901/VCR. The aim of this study was to explore the role of CIAPIN1 in the development of multidrug resistance (MDR) in gastric cancer cells. Upregulation of CIAPIN1 in MDR gastric cancer cells was confirmed by semiquantitative RT-PCR and Western blotting. Using cDNA transfection and RNA interference, we successfully established stable transfectants with upregulation (i.e., SGC7901-pCIAPIN1) or downregulation (i.e., SGC7901-pSiCIAPIN1 and SGC7901/ADR-pSiCIAPIN1) of CIAPIN1 expression, respectively. In vitro drug sensitivity assay demonstrated that overexpression of CIAPIN1 conferred MDR in SGC7901 cells whereas downregulation of CIAPIN1 sensitized SGC7901 and SGC7901/ADR cells to anticancer drugs. CIAPIN1 protected both SGC7901 and SGC7901/ADR cells from ADR-induced apoptosis and reduced intracellular accumulation and retention of adriamycin. Moreover, expression of P-glycoprotein (P-gp or MDR-1, a product of MDR-1 gene) and MDR-related protein-1 (MRP-1) was upregulated by CIAPIN1. In addition, Western blotting revealed that CIAPIN1 decreased the expression of Bcl-2, Bax and p53. Therefore, it is concluded that CIAPIN1 confers MDR in gastric cancer cells, likely by upregulating MDR-1 and MRP-1.
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PMID:CIAPIN1 confers multidrug resistance by upregulating the expression of MDR-1 and MRP-1 in gastric cancer cells. 1641 Jul 21

Hint1 is a member of the evolutionarily conserved family of histidine triad proteins that acts as a haplo-insufficient tumor suppressor inducing spontaneous tumor formation in Hint+/- and Hint-/- mouse models. However, the molecular mechanisms for the tumor-suppressing activity are poorly defined. In this respect, we have recently shown that Hint1, by interaction with Pontin and Reptin, inhibits T-cell factor/beta-catenin-mediated transcription of Wnt target genes. In this study, we have found that, after transient transfection with Hint1, SW480 and MCF-7 cells undergo apoptosis as analyzed by pro-caspase-3 and poly(ADP-ribose) polymerase cleavage, M30 CytoDEATH staining, cytochrome c release, and DNA fragmentation enzyme-linked immunosorbent assay. Hint1 is involved in the regulation of apoptotic pathways by inducing an up-regulation of p53 expression coinciding with an up-regulation of the proapoptotic factor Bax and a concomitant down-regulation of the apoptosis inhibitor Bcl-2. Bad and Puma levels remained unchanged. Further analyses revealed that Hint1 is associated with the Bax promoter and is a component of the Tip60 histone acetyltransferase complex and, in this context, appears to be involved in the regulation of Bax expression. Knockdown of Hint1 by short hairpin RNA resulted in down-regulation of p53 and Bax but had no effect on Bcl-2 expression. A mutant Hint1 (H112N) protein defective in enzymatic activity as an AMP-NH2 hydrolase was not impaired in induction of apoptosis, suggesting that the Hint1 pro-apoptotic activity is independent of the Hint1 enzymatic activity.
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PMID:The histidine triad protein Hint1 triggers apoptosis independent of its enzymatic activity. 1683 43

The tumor-suppressor function of p53 relies on its transcriptional activity, which is modulated by post-translational modifications and interactions with regulatory proteins. The prolyl isomerase Pin1 has a central role in transducing phosphorylation of p53 into conformational changes that affect p53 stability and function. We found that Pin1 is required for efficient loading of p53 on target promoters upon stress. In addition, Pin1 is recruited to chromatin by p53 and stimulates binding of the p300 acetyltransferase and consequent p53 acetylation. Accordingly, tumor-associated mutations at Pin1-binding residues within the p53 proline-rich domain hamper acetylation of p53 by p300. After phosphorylation of p53 at Ser46 triggered by cytotoxic stimuli, Pin1 also mediates p53's dissociation from the apoptosis inhibitor iASPP, promoting cell death. In tumors bearing wild-type p53, expression of Pin1 and iASPP are inversely correlated, supporting the clinical relevance of these interactions.
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PMID:The prolyl isomerase Pin1 orchestrates p53 acetylation and dissociation from the apoptosis inhibitor iASPP. 1791 58


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