Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The MDM2 oncoprotein encodes a 90 kDa nuclear phosphoprotein capable of abrogating the growth suppressive functions of p53 and pRb tumor suppressor proteins by direct interaction. Alternative splicing of MDM2 protein coding sequences has been documented during tumor progression in human ovarian and bladder carcinomas. The aim of this study was to determine whether alternative splicing of MDM2 occurs during breast tumorigenesis in mice and humans and whether protein coding sequences were affected. Specimens representing normal and malignant breast tissues from the murine D2 mammary tumor model system and human breast carcinomas were examined. Three distinct mdm2 mRNA transcripts of 3.3, 1.6 and 1.5 kb were detected in normal and malignant murine mammary tissues by Northern blot analysis using a full-length mdm2 cDNA probe. Additional Northern blot analysis using a probe derived from exon 12 of murine mdm2 demonstrated that the 1.5 and 1.6 kb transcripts lack sequences encoding the C-terminus of the protein. No evidence of internal deletions of protein coding sequences of mdm2 was detected in any of the normal mammary tissues or D2 murine mammary tumors examined by reverse transcription PCR (RT-PCR). Three distinct MDM2 transcripts of 6.7, 4.7 and 1.9 kb were detected in malignant human breast tissue by Northern blot analysis using a cDNA probe specific for the complete open reading frame of human MDM2. However, a cDNA probe specific for the last exon of human MDM2 hybridized only to the 6.7 and 4.7 kb transcripts, demonstrating that the 1.9 kb transcript lacked protein coding sequences contained in exon 12. Similarly, no internal deletions were detected in a panel of malignant human breast tissues using RT-PCR and analogous primers within human MDM2. Therefore, breast tumors differ from other solid tumors reported previously in that no internal deletions of MDM2 protein coding sequences were observed. However, the data document the presence of multiple MDM2 mRNA transcripts in both normal and malignant breast tissues. A subset of MDM2 transcripts were shown to lack the last exon which contains sequences coding for the RING and zinc fingers and domains which are targets for caspase-3 mediated proteolytic degradation and are required to target p53 for proteosomal degradation.
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PMID:Expression of MDM2 during mammary tumorigenesis. 1018 33

Cells undergoing p53-mediated apoptosis activate caspase 3-like activities, resulting in the cleavage of the MDM2 oncoprotein and other apoptotic substrates such as poly(ADP-ribose) polymerase. To investigate the mechanism of p53-mediated apoptosis and to determine whether cleavage of MDM2 has a potential role in regulating p53, we examined caspase activation and cleavage of MDM2 in a cell line undergoing p53-mediated growth arrest and delayed apoptosis. We found that in H1299 cells expressing a temperature-sensitive human p53, a distinct caspase activity specific for the MDM2 cleavage site DVPD is induced by p53 prior to the onset of apoptosis and loss of viability. This is accompanied by the cleavage of MDM2 but not the apoptotic substrate poly(ADP-ribose) polymerase. The cleaved MDM2 loses the ability to promote p53 degradation and may potentially function in a dominant-negative fashion to stabilize p53. These results suggest that p53 activation may induce a positive feedback effect by cleavage of MDM2 through a unique caspase.
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PMID:Activation of an MDM2-specific caspase by p53 in the absence of apoptosis. 1032 37

The oncoprotein MDM2 binds and inactivates p53. MDM2 also binds to the tumor suppressor pRB, as well as E2F-1. E2F-1 is a transcription factor that regulates S phase entry and has been shown to cause apoptosis in some cell types when overexpressed. To investigate the effect of adenovirus-mediated E2F-1 overexpression, MDM2-overexpressing tumor cell lines were treated by mock infection, infection with an adenoviral vector expressing beta galactosidase, or E2F-1 (Ad5CMV-E2F-1). Western blot analysis confirmed significant overexpression of E2F-1 in Ad5CMV-E2F-1-infected cells. E2F-1 overexpression resulted in marked growth inhibition and rapid loss of cell viability. Ad5CMV-E2F-1 infection resulted in early S phase entry, followed by apoptotic cell death. E2F-1 overexpression was associated with a marked decrease in MDM2 levels and no evidence of increased Bax levels, whereas p53 and Bcl-2 levels remained undetectable. Cleavage of poly-ADP-ribose polymerase and caspase 3/CPP32 implicated activation of the caspase cascade in E2F-1-mediated apoptosis. These results indicate that adenovirus-mediated E2F-1 overexpression in MDM2-overexpressing tumor cells results in decreased MDM2 expression and widespread apoptosis. Because MDM2-overexpressing tumors are often resistant to p53 gene therapy, adenovirus-mediated E2F-1 gene therapy may be a promising alternative strategy.
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PMID:Adenovirus-mediated E2F-1 gene transfer inhibits MDM2 expression and efficiently induces apoptosis in MDM2-overexpressing tumor cells. 1047 12

The MDM2 oncoprotein has been shown to inhibit p53-mediated growth arrest and apoptosis. It also confers growth advantage to different cell lines in the absence of p53. Recently, the ability of MDM2 to arrest the cell cycle of normal human fibroblasts has also been described. We report a novel function for this protein, showing that overexpression of MDM2 promotes apoptosis in p53-deficient, human medullary thyroid carcinoma cells. These cells, devoid of endogenous MDM2 protein, exhibited a significant growth retardation after stable transfection with mdm2. Cell cycle distribution of MDM2 transfectants [medullary thyroid tumor (MTT)-mdm2] revealed a fraction of the cell population in a hypodiploid status, suggesting that MDM2 is sufficient to promote apoptosis. This circumstance is further demonstrated by annexin V labeling. MDM2-induced apoptosis is partially reverted by transient transfection with p53 and p19ARF. Both MTT and MTT-mdm2 cells were tumorigenic when injected into nude mice. However, the percentage ofapoptotic nuclei in tumor sections derived from MDM2-expressing cells was significantly higher relative to that in the parental cell line. MDM2-mediated programmed cell death is at least mediated by a down-regulation of the antiapoptotic protein Bcl-2. Protein levels of caspase-2, which are undetectable in the parental cell line, appear clearly elevated in MTT-mdm2 cells. Caspase-3 activation does not participate in MDM2-induced apoptosis, as determined by protein levels or poly(ADP-ribose) polymerase fragmentation. The results observed in this medullary carcinoma cell line show for the first time that the product of the mdm2 oncogene mediates cell death by apoptosis in p53-deficient tumor cells.
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PMID:The MDM2 oncoprotein promotes apoptosis in p53-deficient human medullary thyroid carcinoma cells. 1061 65

Cisplatin-induced apoptosis in epithelial ovarian cancer cells is in part a consequence of suppressed Xiap expression and upregulation of the Fas/FasL system. Changes in the expression of these 'cell death' and 'cell survival' genes lead to activation of caspase-3, and cleavage of MDM2 and FAK. Failure of cancer cells to maintain a balance in the expression of these genes in favor of apoptotic cell death may be an important factor of chemoresistance. Xiap may be a novel target for gene therapy of human ovarian epithelial cancer and, dependent on P53 status, expression of Xiap antisense alone or in combination with wild-type P53 sense may offer a new approach for the treatment of the chemoresistant cancer.
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PMID:Apoptosis and chemoresistance in human ovarian cancer: is Xiap a determinant? 1081 Feb 7

The mechanism(s) of c-Myc transcription factor-induced apoptosis is still obscure. The activation of c-Myc has been found to lead into the processing/activation of caspases (caspase-3), but the significance of this for the cell demise is debatable. Here we report that several targets of caspases (PKCdelta, MDM2, PARP, replication factor C, 70 kDa U1snRNP, fodrin and lamins) are cleaved during c-Myc-induced apoptosis in Rat-1 MycER cells, indicating an important role for caspases in the apoptotic process. We further found that the ATM (ataxia telangiectasia mutated)--protein is a novel key substrate of caspases. In in vitro assays, purified recombinant ATM protein was found to be cleaved by the effector caspases 3 and 7. The functional significance of the ATM cleavage is supported by the finding that ectopic expression of ATM protected in part against apoptosis. We also show that c-Myc-induced apoptosis involves loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria into the cytosol and subsequent processing of caspase-9. The cleavage of caspase-9 is, however, minimal and a much later event than the processing/activation of caspase-3, suggesting that it is not the apical caspase. Evidence is provided that there is, nevertheless, an upstream caspase(s) regulating the functions of caspase-3 and mitochondria. Additionally, it was found that p53 becomes upregulated, together with its transcriptional targets MDM2 and p21, upon c-Myc induction, but this occurs also at a later time than the activation of caspase-3.
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PMID:Caspases and mitochondria in c-Myc-induced apoptosis: identification of ATM as a new target of caspases. 1082 87

Cisplatin-centered chemotherapy is a key treatment for ovarian cancer, but resistance to chemotherapeutic agents remains a major cause of treatment failure. Multiple factors are known to contribute to the development of this chemoresistance. Although it has been demonstrated that X-linked inhibitor of apoptosis protein (Xiap) prevents apoptosis by inhibiting effector caspases, if and how it is important in chemoresistance in ovarian cancer has not been studied. The effects of Xiap down-regulation and/or restoration of wild type p53 by recombinant adenovirus infection were examined on four ovarian epithelial cancer cell lines [C13*, A2780-s (wild type p53), A2780-cp (mutant p53), and SKOV3 (null p53)]. Apoptosis and protein expression (e.g., Xiap, caspase-3, p53, MDM2, and p21waf1) were assessed by Hoechst 33258 stain and Western blot, respectively. We demonstrated that Xiap down-regulation following adenoviral antisense expression induces apoptosis in the wild-type p53 cells, but not in the mutated or null cells. Xiap down-regulation resulted in caspase-3 activation, caspase-mediated MDM2 processing, and p53 accumulation. Restoration of wild type p53 in the p53-mutated or -null cells significantly enhanced the proapoptotic effect of Xiap antisense expression. Down-regulation of Xiap induced apoptosis in chemoresistant ovarian cancer cells, a process dependent on p53 status.
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PMID:Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. 1105 57

MDM2 is a substrate of caspase-3 in p53-mediated apoptosis. In addition, MDM2 mediates its own ubiquitination in a RING finger-dependent manner. Thus, we investigated whether MDM2 is degraded through a ubiquitin-dependent proteasome pathway in the absence of p53. When HL-60 cells, p53 null, were treated with etoposide, MDM2 was markedly decreased prior to caspase-3-dependent retinoblastoma tumor suppressor protein (pRb) and poly (ADP- ribose) polymerase (PARP) cleavages. Moreover, down-regulation of MDM2 level was not coupled with its mRNA down-regulation. However, the level of MDM2 was partially restored by proteasome inhibitors such as LLnL and lactacystin, even in the presence of etoposide. Our results suggest that, in the p53 null status, MDM2 protein level is decreased by proteasome-mediated proteolysis prior to caspase-3-dependent PARP and pRb cleavages.
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PMID:The levels of MDM2 protein are decreased by a proteasome-mediated proteolysis prior to caspase-3-dependent pRb and PARP cleavages. 1130 36

The tumor suppressor p53 is known to regulate gene transcription and apoptosis in mammalian cells. In the present study we ascertain whether these events are mutually dependent and obligatorily linked for induction of apoptosis of ventricular myocytes. Adenovirus mediated gene delivery of wild p53 (p53WT) or a mutant form of p53 (p53MT) defective for gene transcription to ventricular myocytes was confirmed by Western blot analysis. A significant increase in the p53 dependent genes Bax and MDM2 was observed with p53WT but not p53MT. Nuclear DNA visualized by agarose gel electrophoresis revealed nucleosomal DNA laddering in the presence of either p53 protein. Apoptosis was substantiated by Hoechst 33258 nuclear staining. Perturbations to mitochondria consistent with the mitochondrial death pathway, including loss of mitochondrial transmembrane potential Delta(psi)m and cytochrome c release were observed with p53WT and p53MT. An increase in caspase 3-like activity was noted with either p53WT or p53MT protein that was suppressed by the caspase 3 inhibitor Ac-DEVD-CHO. To our knowledge the experiments described here provide the first indication that p53 activates the mitochondrial death pathway and provokes apoptosis of ventricular myocytes independent of DNA binding and de novo gene activation.
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PMID:p53 activates the mitochondrial death pathway and apoptosis of ventricular myocytes independent of de novo gene transcription. 1144 32

The p53 tumor suppressor pathway is disrupted by human papillomavirus (HPV) in most cervical cancer cells. The E6 proteins, which could mediate p53 degradation, are related to cellular immortalization, transformation, and tumor formation. In order to study the E6 abrogated p53 function in stress, we transfected HPV-16 E6 gene to TK6 cells in this study. Here we showed that HPV-16 E6 mRNA levels decreased in a dose dependent manner after sodium arsenite (SA) treatment, but not after X-irradiation. P53, p21, and MDM2 were induced in E6-transfected TK6 cells, as well as in parental TK6 cells after arsenite treatment. But the above proteins were only induced in TK6 cells after X-irradiation. It indicated that arsenite, but not X-ray, could suppress the transcription of E6 gene and therefore activate the p53 tumor suppressor pathway in TK6-E6 cells. After arsenite treatment, TK6-E6 cells showed more sub-G1 apoptosis, activated caspase-3/CPP32 fragment, DNA ladder, and less viability than parental TK6 cells, indicating that arsenite enhanced apoptosis in E6-transfected TK6 cells. In contrast, after X-irradiation, TK6-E6 cells showed less sub-G1 apoptosis and higher viability than parental TK6 cells. Thus, it would be another possible strategy to promote arsenite as another potential candidate for the therapeutic purpose in HPV-positive cancer cells.
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PMID:Sodium arsenite suppresses human papillomavirus-16 E6 gene and enhances apoptosis in E6-transfected human lymphoblastoid cells. 1181 66


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