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)

The Cdk inhibitor p21 regulates p53-mediated growth arrest following DNA damage. It is expressed during epithelial differentiation in a variety of organs including colon. We investigated susceptibility of p21-deficient mice to the colon carcinogen azoxymethane (AOM). After AOM injections, rodents develop putative premalignant lesions called aberrant crypt foci (ACF) that are localized to the distal three centimeters of the colon. p21-deficient mice developed significantly higher numbers of ACF than wild-type mice in response to AOM, and these were not restricted to distal colon. After AOM treatment, increased numbers of lymphoid aggregates were detected in p21-deficient colon. Proliferation was similar in wild type and p21-deficient colon before and after AOM injection, but AOM-induced apoptosis was detected only in wild-type crypt epithelial cells, and not in the p21-deficient colon. The proapoptotic function uncovered for p21 was unexpected, because p21 acts as an inhibitor of apoptosis in many systems, and is not required for p53-dependent apoptosis. Enhanced formation of ACF in p21-deficient mice supports a tumor suppressor function for p21 in the colon. Reduced apoptosis of colon epithelial cells with deleterious mutations may be an initiating event in the formation of ACF, with inflammatory cell cytokine expression contributing to their further expansion.
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PMID:Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon. 1537 95

The survivin protein contains structural features of the inhibitor of apoptosis protein family. Previous studies have suggested that survivin is essential for cell survival because it counteracts an otherwise constitutive propensity to apoptosis during mitosis. In addition, survivin appears to be a component of the chromosomal passenger protein complex that participates in multiple facets of cell division. Here we report that euploid human cells do not die in the absence of survivin. Instead, depletion of survivin caused defects in cell division, followed by an arrest of DNA synthesis due to activation of a checkpoint involving the tumor suppressor protein p53. During anaphase mitosis in survivin-deficient cells, sister chromatids disjoined normally, but one or more of the sister chromatids frequently lagged behind the main mass of segregating chromosomes, probably because of merotelic kinetochore attachments. Survivin-deficient cells initiated but failed to complete cytokinesis, apparently because the spindle midzone and midbody microtublues were absent during late mitosis. The abnormalities of both chromosome segregation and cytokinesis could be attributed to a defect in the chromosomal passenger protein complex, with a consequent mislocalization of the kinesin-like motor protein MKLP-1 playing a more immediate role in the microtubule abnormalities. Depletion of another chromosomal passenger protein, aurora-B, recapitulated the survivin RNA interference phenotypes. We conclude that survivin can be essential for the proliferation of normal human cells by virtue of its contributions to accurate sister chromatid segregation and assembly/stabilization of microtubules in late mitosis. However, the protein is not inevitably required for the survival of normal cells.
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PMID:Cell division and cell survival in the absence of survivin. 1547 1

When added for a short period (2-4 h) to cells, the kinase inhibitor staurosporine (STS), can trigger double strand breaks, the formation of nuclear foci containing phosphorylated H2AX, Chk2, and p53, a decrease in transcription, and a minor degree of peripheral chromatin condensation. This "preapoptotic chromatin condensation" (PACC) occurs before mitochondrial membrane permeabilization (MMP) and caspase activation become detectable and is not inhibited by Z-VAD-fmk or Bcl-2. PACC is followed by classical apoptosis, when cells are cultured overnight, even when STS is removed from the system. After overnight incubation, STS-pretreated cells manifest mitochondrial cytochrome c release, caspase activation, phosphatidylserine exposure, and apoptotic DNA fragmentation. Caspase or MMP inhibitors did not influence the advent of PACC yet did suppress the evolution of PACC toward apoptosis. Importantly, two unrelated MMP inhibitors (viral mitochondrial inhibitor of apoptosis (vMIA) from cytomegalovirus and mitochondrion-targeted Bcl-2) had a larger range of effects than the pan-caspase inhibitor Z-VAD-fmk. Caspase inhibition simply prevented the transition from PACC to apoptosis yet did not reverse PACC and did not restore transcription. In contrast, Bcl-2 and vMIA allowed for the repair of the DNA lesions, correlating with the reestablishment of active transcription. PACC could also be induced by a gross perturbation of RNA synthesis or primary DNA damage. Again, inhibition of MMP (but not that of caspases) reversed PACC induced by these stimuli. In synthesis, our data reveal the unexpected capacity of STS to induce DNA lesions and suggest qualitative differences in the cytoprotective and DNA repair-inducing potential of different apoptosis inhibitors.
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PMID:Preapoptotic chromatin condensation upstream of the mitochondrial checkpoint. 1549 71

The overexpression of the inhibitor of apoptosis protein, survivin, may provide tumor cells with a distinct survival advantage in situ; hence, therapeutic strategies have been designed to inhibit its expression. In this study, we ectopically expressed the interferon regulatory factor (IRF)-1 protein in the breast carcinoma cell lines MDA-MB-468 and SK-BR-3 using a recombinant adenovirus (Ad-IRF-1). By screening microarray analysis of cDNA from the human breast cancer cell line MDA-MB-468 infected with Ad-IRF-1, we observed a 15-fold down-regulation of the survivin gene when compared with uninfected cells. Consequently, we tested survivin expression in Ad-IRF-1-infected MDA-MB-468 and SK-BR-3 breast cancer cell lines. Immunoblotting analyses supported the contention that ectopic expression of the IRF-1 protein results in down-regulation of survivin protein expression that is independent of p53. In addition, Ad-IRF-1 infection of these human breast cancer cell lines induces the expression of p21. We also report that increased apoptosis is observed in tumor cells infected with Ad-IRF-1 compared with Ad-Psi5 mock-infected cells and that cell death is further augmented when the IRF-1-infected cells are cultured with Adriamycin. Moreover, in a xenogeneic mouse model of breast carcinoma, in vivo treatment of tumor-bearing mice with intratumoral Ad-IRF-1 injections results in tumor growth inhibition. In resected tumors from mice that had been treated with Ad-IRF-1, tumor cells that express the IRF-1 transgene have a predominant IRF-1-positive, survivin-negative phenotype. Collectively, these observations suggest that therapies designed to enhance IRF-1 expression within tumor cells may represent novel treatment strategies for breast cancer.
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PMID:Ectopic expression of interferon regulatory factor-1 promotes human breast cancer cell death and results in reduced expression of survivin. 1554 8

The role of Daxx, in particular its ability to promote or hinder proliferation, still remains controversial. In order to elucidate the functional relevance of Daxx in malignant myelocytes, the erythroleukemia cell line HEL was stably transfected with a Daxx-expressing vector or with the respective Daxx-negative control vector. Assessing the molecular consequences of ectopic Daxx-expression, we present evidence that Daxx downregulates p53. Moreover, we demonstrate that Daxx overexpressing myelocytes downregulate the proapoptotic Bcl-2 family member Bax, while expression of antiapoptotic Bcl-2 is not influenced. Furthermore, expression of Daxx diminishes expression levels of the initiator-procaspase-8 and -10, and the executioner procaspase-7, whereas the procaspase-3, -6 and -9 remain unaltered. The altered protein levels of the caspases in Daxx overexpressing myelocytes are accompanied by a decrease of expression levels of the inhibitor of apoptosis proteins (IAPs) cIAP-1, -2 and survivin. Despite the described impact of Daxx expression on major molecules of the apoptotic cascade, expression of Daxx in neoplastic myelocytes does not impact on the rate of proliferation. Upon a proapoptotic stimulus such as serum withdrawal Daxx is unable to maintain its influence on expression levels of p53, Bax, IAPs and the procaspase-8, -10 and -7.
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PMID:In malignant myeloid cells expression of Daxx downregulates expression of p53 and of the inhibitors of apoptosis proteins. 1557 Feb 94

Taxol is one of the most successful drugs for the treatment of cancer because of its ability to target tubulin, block cell cycle progression at mitosis, and induce apoptosis. Despite the success of Taxol, the development of drug resistance hampers its clinical applicability. Herein we report that beta-tubulin mutant, Taxol-resistant ovarian cancer cells exhibit defective mitotic response to Taxol, even at high concentrations that are sufficient to trigger apoptosis. This mitotic response-defective phenotype is independent of p53 status. We have found that survivin, the mitosis regulator and inhibitor of apoptosis protein, is deregulated in these Taxol-resistant cancer cells; Taxol fails to induce survivin levels and survivin phosphorylation in these cells, in contrast to their parental drug-sensitive counterparts. Exogenous expression of wild-type survivin is able to restore the mitotic response of the resistant cells to Taxol treatment. On the other hand, exogenous expression of dominant-negative survivin abrogates the Taxol-induced mitotic response in drug-sensitive cancer cells. We have also found that overexpression of the mitotic kinase Cdk1, which phosphorylates survivin, is unable to restore the Taxol-induced mitotic response in the resistant cells. Our results show the importance of survivin for the mitotic response in the context of Taxol resistance and provide novel insights into the mechanisms of mitotic arrest and apoptosis induced by microtubule-targeting agents.
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PMID:Survivin deregulation in beta-tubulin mutant ovarian cancer cells underlies their compromised mitotic response to taxol. 1557 81

Understanding of the mechanism of ultraviolet (UV)-mediated cutaneous damages is far from complete. The cancer-specific expression of Survivin, a member of the inhibitor of apoptosis family of proteins, coupled with its importance in inhibiting cell death and in regulating cell division, makes it a target for cancer treatment. This study was designed to investigate the modulation of Survivin during UV response, both in vitro and in vivo. We used UV-B-mediated damages in normal human epidermal keratinocytes (NHEK) cells as an in vitro model and SKH-1 hairless mouse model for the in vivo studies. For in vitro studies, NHEK were treated with UV-B and samples were processed at 5, 15, 30 min, 1, 3, 6, 12 and 24 h after treatment. Our data demonstrated that UV-B exposure (50 mJ/cm2) to NHEK resulted in a significant upregulation in Survivin messenger RNA (mRNA) and protein levels. We also observed that UV-B exposure to NHEK resulted in significant (1) decrease in Smac/DIABLO and (2) increase in p53. For in vivo studies, the SKH-1 hairless mice were subjected to a single exposure of UV-B (180 mJ/cm2), and samples were processed at 3, 6, 12 and 24 h after UV-B exposure. UV-B treatment resulted in a significant increase in protein or mRNA levels (or both) of Survivin, phospho-Survivin and p53 and a concomitant decrease in Smac/DIABLO in mouse skin. This study demonstrated, for the first time, the involvement of Survivin (and the associated events) in UV-B response in vitro and in vivo in experimental models regarded to have relevance to human situations.
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PMID:Ultraviolet-B radiation causes an upregulation of survivin in human keratinocytes and mouse skin. 1562 49

Baculoviral inhibitor of apoptosis repeat-containing (Birc)6 gene/BIRC6 (Bruce/APOLLON) encodes an inhibitor of apoptosis and a chimeric E2/E3 ubiquitin ligase in mammals. The physiological role of Bruce in antiapoptosis is unknown. Here, we show that deletion of the C-terminal half of Bruce, including the UBC domain, causes activation of caspases and apoptosis in the placenta and yolk sac, leading to embryonic lethality. This apoptosis is associated with up-regulation and nuclear localization of the tumor suppressor p53 and activation of mitochondrial apoptosis, which includes up-regulation of Bax, Bak, and Pidd, translocation of Bax and caspase-2 onto mitochondria, release of cytochrome c and apoptosis-inducing factor, and activation of caspase-9 and caspase-3. Mutant mouse embryonic fibroblasts are sensitive to multiple mitochondrial death stimuli but resistant to TNF. In addition, eliminating p53 by RNA interference rescues cell viability induced by Bruce ablation in human cell line H460. This viability preservation results from reduced expression of proapoptotic factors Bax, Bak, and Pidd and from prevention of activation of caspase-2, -9, and -3. The amount of second mitochondrial-derived activator of caspase and Omi does not change. We conclude that p53 is a downstream effector of Bruce, and, in response to loss of Bruce function, p53 activates Pidd/caspase-2 and Bax/Bak, leading to mitochondrial apoptosis.
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PMID:The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development. 1564 Mar 52

X-linked inhibitor of apoptosis (XIAP) is the most potent member of the inhibitor of apoptosis protein (IAP) gene family in terms of its ability to inhibit caspases and suppress apoptosis. Recent evidence has suggested that XIAP is a key determinant in chemoresistance of cancer cells. To explore a novel approach for ameliorating chemotherapy of gastric cancer, the antisense expression vector for the XIAP gene was constructed and transferred into gastric cancer cell lines, MKN-45 (wild-type p53) and MKN-28 (mutant-type p53). This transfer resulted in significant downregulation of XIAP expression, decreased in vitro cell viabilities, and induced apoptosis. In transferred cells, inactive caspase-3 precursors were cleaved into the active subunits (p20 and p17) during apoptosis induced by downregulation of XIAP. The inhibitory effects of cisplatin and mitomycin C on the growth of XIAP downregulated cancer cells were significantly enhanced. In addition, this process occurred only in wild-type p53 (MKN-45), but not in mutant-type p53 (MKN-28) gastric cancer cells. The data presented suggest that downregulation of XIAP via antisense RNA can lead to apoptosis of gastric cancer cells in vitro, correlating with cellular p53 status and activation of caspase-3. This finding could lead to a potential strategy for improving the efficiency of therapies for gastric cancer.
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PMID:Downregulation of XIAP expression induces apoptosis and enhances chemotherapeutic sensitivity in human gastric cancer cells. 1570 55

Evasion of apoptotic cell death plays a key role in cancer development. Survivin is a member of the inhibitor of apoptosis proteins, which also has a role in the control of cell division. Survivin may be overexpressed in some tumors and has been suggested to be related to PTEN, beta-catenin, p53 [all of them frequently abnormal in endometrial carcinomas (ECs)], and STAT-3. A tissue microarray was constructed from paraffin-embedded blocks of 95 ECs, previously studied for microsatellite instability and for alterations in PTEN, k-RAS, and CTNNB-1. Immunohistochemical evaluation included 1) survivin, 2) markers of cell proliferation and apoptosis (Ki67-MIB1 and M 30-neoepitope cytokeratin 18), and 3) proteins involved in cell signaling pathways (PTEN, phospho-AKT, beta-catenin, p53, and STAT-3). Survivin expression was frequent in ECs (75.95%) but did not show any statistical significant correlation with histological type and grade, stage, overall survival, or mitotic and apoptotic indexes. Survivin expression had a statistical significant correlation with decreased PTEN expression (r = -0.383, p = 0.001), increased phospho-AKT (r = 0.70, p < 0.001), and positive STAT-3 immunostaining (r = 0.6, p < 0.001). Survivin expression did not show statistical correlation with either beta-catenin or p53 alterations. The results suggest that increased survivin expression is frequent in ECs and may be dependent on STAT-3 and PI3 K/AKT activation. Because PTEN abnormalities are very frequent in ECs, the results from this study indicate that PTEN may interfere with the process of apoptosis and cell proliferation by promoting survivin expression.
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PMID:Survivin expression in endometrial carcinoma: a tissue microarray study with correlation with PTEN and STAT-3. 1596


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