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)

Lactotroph cell death is increased in streptozotocin-induced diabetic rats. To determine the mechanism involved, cell death proteins were accessed in pituitaries of diabetic (streptozotocin at 65 mg/kg, 2 months evolution) and control male rats by Western blot analysis and double immunohistochemistry. The intact and cleaved forms of caspase 9 were increased in diabetic rat pituitaries compared with controls. Although the proforms of caspases 3, 6, and 7 were increased in diabetic rat pituitaries, their activated forms were either unchanged or decreased. Activation of these effector caspases may be blocked by the increased expression of X-chromosome-linked inhibitor of apoptosis protein (XIAP) in diabetic rat pituitaries. However, in diabetic rats, XIAP expression in lactotrophs was decreased, suggesting that this cell type is not protected. Caspase 8, p53, and nuclear factor kappaB were more highly activated in diabetic rat pituitaries, with caspase 8 colocalization in lactotrophs being increased. These results suggest that, in the pituitaries of diabetic rats, the cascades of normal cell turnover are partially inhibited, possibly via XIAP, and this may be cell specific. Furthermore, activation of the extrinsic cell-death pathway, including activation of caspase 8, may underlie the diabetes-associated increase in lactotroph death.
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PMID:Activation of caspase 8 in the pituitaries of streptozotocin-induced diabetic rats: implication in increased apoptosis of lactotrophs. 1597 52

Alterations in cell proliferation and cell death are essential determinants in the pathogenesis and progression of several diseases such as cancer, neurodegenerative disorders or autoimmune diseases among others. Complex networks of regulatory factors determine whether cells proliferate or die. Recent progress in understanding the molecular changes offer the possibility of specifically targeting molecules and pathways to achieve more effective and rational therapies. Drugs that target molecules involved in apoptosis are used as treatment against several diseases. Candidates such as TNF death receptor family, caspase inhibitors, antagonists of the p53-MDM2 interaction, NF-kappaB and PI3K pathways and Bcl-2 family members have been targeted as cancer cell killing agents. Moreover, apoptosis of tumor cells can also be achieved by targeting the inhibitor of apoptosis proteins, IAPs, in addition to the classical antiproliferative approach. Disruption of STAT activation and interferon beta therapy have been used as a treatment to prevent the progression of some autoimmune diseases. In models of Parkinson's, Alzheimer's and amyotrophic lateral sclerosis, blocking of Par-4 expression or function, as well as caspase activation, prevents neuronal cell death. Finally, it has been shown that gene therapy may be an encouraging approach for treatment of neurodegenerative disorders.
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PMID:Modulating apoptosis as a target for effective therapy. 1609 9

Survivin is a member of the inhibitor of apoptosis protein (IAP) family that is specifically overexpressed in cancer tissues. p53 is one of the tumor suppressor genes; its induction in response to DNA damage causes apoptosis and correlates with drug sensitivity. To investigate the possible regulation of survivin by p53, we examined the level of survivin expression in lung cancer cell lines in response to adriamycin. Levels of survivin mRNA and protein in cell lines with wild-type p53 decreased dramatically after p53 induction, but no such reduction of survivin was observed in cell lines with mutated or null p53. Inhibition of wild-type p53 in A549 cells by small interfering (si) RNA significantly upregulated the expression of survivin. Survivin inhibition by siRNA in PC9 cells with mutated p53 significantly depressed cell proliferation. To investigate the sensitivity of cancer cells to adriamycin after inhibition of survivin, we depressed survivin expression using siRNA, and then added adriamycin at an IC50 dose. After a further 48 hr incubation with adriamycin, proliferation was significantly depressed in the cells treated with siRNA targeting survivin, in comparison with siRNA targeting scramble. Furthermore, both TUNEL and pro-caspase3 expression assay showed a significant increase in apoptosis after combined treatment with adriamycin and siRNA targeting survivin. Our results demonstrate that survivin is downregulated by p53, and that siRNA targeting of survivin increases cell sensitivity to adriamycin and promotes apoptosis. siRNA targeting of survivin could be potentially useful for increasing sensitivity to anticancer drugs, especially in drug-resistant cells with mutated p53.
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PMID:Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to adriamycin. 1610 13

We investigated the effects of ircinin-1, a lipid compound (a C25 sesterterpene tetronic acid) isolated from marine sponges (Sarcotragus sp.), on the modulation of cell cycle and induction of apoptosis in SK-MEL-2 human skin cancer cells (mutant p53). Ircinin-1 treatment on SK-MEL-2 cells resulted in a dose-dependent inhibition of cell growth and induced apoptotic cell death. Flow cytometric analysis revealed that ircinin-1 resulted in G1 arrest in cell cycle progression which was associated with a marked decrease in the protein expression of D-type cyclins and their activating partners Cdk 4 and 6 with concomitant inductions of p21WAF1/CIP1 and p27KIP1. The induction of p21WAF1/CIP1 appears to be transcriptionally upregulated and is p53-independent. In addition, ircinin-1 suppressed the phosphorylation of pRb protein and increased the co-association of pRb or proliferating cell nuclear antigen (PCNA) with p21WAF1/CIP1 in these cells. Ircinin-1 treatment also resulted in induction of apoptosis as determined by morphological changes, DNA fragmentation, alternated ratio of Bax/Bcl-2, cleavages of poly(ADP-ribose) polymerase and PLC-gamma1, and flow cytometric analysis. Ircinin-1 also induced cytochrome c release, cleavage activations of caspase-3 and -9, and upregulation of Fas and Fas-L. Even though the inhibitor of apoptosis protein (IAP) was expressed in ircinin-1-untreated or -treated SK-MEL-2 cells, only the level of cIAP-1, but not XIAP or cIAP-2, was decreased during ircinin-1-induced apoptosis at Western blot and RT-PCR studies. Taken together, these findings suggest that ircinin-1 has strong potential for development as an agent for prevention against skin cancer.
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PMID:Ircinin-1 induces cell cycle arrest and apoptosis in SK-MEL-2 human melanoma cells. 1616 5

Resistance to current treatment regimens, such as radiation therapy, remains a major concern in oncology and may be caused by defects in apoptosis programs. Because inhibitor of apoptosis proteins (IAPs), which are expressed at high levels in many tumors, block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic modulation of IAPs could target a key control point in resistance. Here, we report for the first time that full-length or mature second mitochondria-derived activator of caspase (Smac), an inhibitor of IAPs, significantly enhanced gamma-irradiation-induced apoptosis and reduced clonogenic survival in neuroblastoma, glioblastoma, or pancreatic carcinoma cells. Notably, Smac had no effect on DNA damage/DNA repair, activation of nuclear factor-kappaB, up-regulation of p53 and p21 proteins, or cell cycle arrest following gamma-irradiation, indicating that Smac did not alter the initial damage and/or cellular stress response. Smac enhanced activation of caspase-2, caspase-3, caspase-8, and caspase-9, loss of mitochondrial membrane potential, and cytochrome c release on gamma-irradiation. Inhibition of caspases also blocked gamma-irradiation-induced mitochondrial perturbations, indicating that Smac facilitated caspase activation, which in turn triggered a mitochondrial amplification loop. Interestingly, mitochondrial perturbations were completely blocked by the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone or the relatively selective caspase-2 inhibitor N-benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethylketone, whereas caspase-8 or caspase-3 inhibitors only inhibited the increased drop of mitochondrial membrane potential provided by Smac, suggesting that caspase-2 was acting upstream of mitochondria after gamma-irradiation. In conclusion, our findings provide evidence that targeting IAPs (e.g., by Smac agonists) is a promising strategy to enhance radiosensitivity in human cancers.
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PMID:Sensitization for gamma-irradiation-induced apoptosis by second mitochondria-derived activator of caspase. 1628 43

Colorectal cancer arises as a result of the accumulation of genetic errors many of which affect the control of apoptosis. Effective chemoprevention strategies for colorectal cancer must rectify these genetic defects. Mutation of apc is often the initiating genetic lesion in colorectal cancers that develop along the chromosomal instability pathway. Depending on the cellular context, loss of apc activates the Wnt signalling pathway causing immediate widespread apoptosis of colorectal epithelial cells and defects in differentiation and cell migration. Only cells that are inherently resistant to apoptosis survive this initial wave of apoptosis. These surviving cells constitute the epithelial population that develop into adenomas. Two gene targets of the Wnt signalling pathway are of particular relevance to apoptosis. Although controversial, survivin may function to inhibit apoptosis. MYC has two outputs in normal cells, the induction of apoptosis and proliferation. These opposing functions work so that MYC can only induce cell proliferation in cells if apoptosis is disabled. p53 couples apoptosis to mitogenic signals and survival pathways. Under some circumstances, NF-kappaB can act as an inhibitor of apoptosis possibly through increased expression of bcl-x(L). Tumours that evolve by the microsatellite instability pathway often have mutations in the proapoptotic gene bax. Colonic adenomas express cyclo-oxygenase-2 (COX-2) and may be targets of chemoprevention before the development of malignancy. However, the recent discovery that coxibs increase the risk of serious cardiovascular events limits their use as chemopreventive agents. Nevertheless, aspirin remains a drug of great interest as it is already known to reduce the risk of colorectal cancer by up to 50%. The balance of evidence shows that high vegetable fibre diets can prevent colorectal cancer, probably via the fermentation of butyrate enhancing the apoptotic response to DNA damage.
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PMID:An overview of apoptosis and the prevention of colorectal cancer. 1632 9

The regulation of apoptosis, as a distinctive form of programmed cell death, in multistep Barrett's esophagus (BE) carcinogenesis is poorly understood. The aim of this study was to investigate, in the intestinal metaplasia-dysplasia-carcinoma sequence, the role of survivin, an inhibitor of apoptosis; the p53 protein, a tumor suppressor gene involved in cell cycle control; and caspase 3, a protease-inducing apoptosis and inhibited by survivin. Immunohistochemical expression was tested in 40 cases of BE, including 11 low-grade and 19 high-grade dysplasias (HGD), and samples were obtained from 40 surgical specimens of esophagectomy performed for HGD or Barrett's adenocarcinoma. To define the deregulation time of the proteins, overexpression was evaluated in relation to the proliferative and/or maturative compartment. In BE, cytoplasmic expression of survivin and caspase 3 (100% of cases) was significantly higher than expression of p53 (25%). The latter increased with increasing grade of dysplasia. In BE, the expression of survivin, p53, and caspase 3 mainly involved the proliferative compartment, whereas in LGD and HGD, the 3 proteins were coexpressed in both proliferative and maturative compartments. These results indicate that survivin overexpression is an early event in the proliferative compartment of BE, preceding both p53 accumulation and dysplastic changes. Cytoplasmic survivin location may indicate an initial antiapoptotic, more than proliferative, role in the early phases of Barrett carcinogenesis. Expression of caspase 3 in BE and dysplasia may be ascribed to accumulation of the nonactivated form, as the antibody used detects both cleaved and uncleaved caspase 3.
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PMID:Expression of survivin, p53, and caspase 3 in Barrett's esophagus carcinogenesis. 1636 Apr 11

Survivin has recently been identified as a novel member of the inhibitor of apoptosis (IAP) gene family. The product of this gene not only suppresses apoptosis but also controls cell division. Survivin is undetectable in most terminally differentiated normal tissues but is expressed in embryonic and fetal organs and is present in most malignant tumours. Human papillomaviruses (HPV) are thought to play an important role in the development of cervical cancer. By interfering in the cell cycle, the viral oncoproteins (E6 and E7) can induce the immortalization of the host cell. The transcriptional effects of the HPV-16 E6 and E7 proteins on the survivin promoter in transiently transfected cell lines using luciferase tests were examined. HPV-16 E6, but not E7, was found to significantly transactivate the survivin promoter. Experiments performed in different cancer cell lines and with different E6 mutants indicated that the effect of E6 on the survivin promoter is largely dependent on p53 status. In accordance with this, the p53 tumour suppressor protein downregulated the expression of survivin. As E6 is able to interact with p53 and induces its ubiquitin-dependent degradation, it appears that the transactivation effect of E6 on survivin is mediated by the p53 degradation pathway. Transduction of HPV-16 E6 and E7 into human embryonic fibroblast cells showed that the HPV oncoproteins can upregulate endogenous survivin mRNA. Importantly, cell cycle synchronization experiments showed that the effect of HPV-16 E6 on survivin transcription is independent of the cell cycle.
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PMID:Effects of human papillomavirus type 16 oncoproteins on survivin gene expression. 1643 13

The efficiency of anticancer therapy is often restricted by the development of drug resistance. Here, we report that the doxorubicin (DOX)-resistant MCF-7/Adr cells were more resistant to DOX-treatment than MCF-7 cells. However, an alternative treatment of DOX/TNF-alpha enhanced the cytotoxic effect in multidrug resistant MCF-7/Adr cell line. Treatment of cells with TNF-alpha following doxorubicin (DOX) resulted in a decrease of the activated Rel A/p65 in nuclei. Histone deacetylase 1 (HDAC1) was found to interact with Rel A/p65 in the complex, suggesting that HDAC1 is involved in mediating nuclear export of Rel A/p65. The combined treatment of TNF-alpha/DOX also resulted in a significant decrease of mRNA levels of anti-apoptotic genes, such as the cellular inhibitor of apoptosis-1 (c-IAP1), and the long isoform of B cell leukemia/lymphoma x gene (Bcl-xL), leading to efficient induction of caspase-8 cleavage and cell death. In previous work, we demonstrated that TNF-alpha promotes DOX-induced cell death and anti-cancer effect through downregulation of p21 in p53-deficient tumor cells. Thus, we proposed that alternative administration of TNF-alpha and DOX may be a new and efficient therapeutic strategy for patients that develop resistance to cytotoxic treatment.
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PMID:A combined treatment TNF-alpha/doxorubicin alleviates the resistance of MCF-7/Adr cells to cytotoxic treatment. 1648 79

Akt is a determinant of cisplatin [cis-diammine-dichloroplatinum (CDDP)] resistance in ovarian cancer cells, and this may be related to the regulation of p53. Precisely how Akt facilitates CDDP resistance and interacts with p53 is unclear. Apoptotic stimuli induce second mitochondria-derived activator of caspase (Smac) release from mitochondria into the cytosol, where it attenuates inhibitor of apoptosis protein-mediated caspase inhibition. Whereas Smac release is regulated by p53 via the transactivation of proapoptotic Bcl-2 family members, it is unclear whether p53 also facilitates Smac release via its direct mitochondrial activity. Here we show that CDDP induces mitochondrial p53 accumulation, the mitochondrial release of Smac, cytochrome c, and HTR/Omi, and apoptosis in chemosensitive but not in resistant ovarian cancer cells. Smac release was p53 dependent and was required for CDDP-induced apoptosis. Mitochondrial p53 directly induced Smac release. Akt attenuated mitochondrial p53 accumulation and Smac/cytochrome c/Omi release and conferred resistance. Inhibition of Akt facilitated Smac release and sensitized chemoresistant cells to CDDP in a p53-dependent manner. These results suggest that Akt confers resistance, in part, by modulating the direction action of p53 on the caspase-dependent mitochondrial death pathway. Understanding the precise etiology of chemoresistance may improve treatment for ovarian cancer.
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PMID:Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway. 1654 Jun 63


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