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

Persistent infection with oncogenic human papillomaviruses (HPVs) is the most important factor in the induction of uterine cervical cancer, a leading cause of cancer mortality in women worldwide. Upon cell transformation, continual expression of the viral oncogenes is required to maintain the transformed phenotype. The viral E6 protein forms a ternary complex with the cellular E6-AP protein and p53 protein which promotes the rapid degradation of p53. Recent studies have revealed that lignans from the creosote bush (3'-O-methyl-nordihydroguaiaretic acid) can repress the viral promoter responsible for E6 gene expression. Work reported here shows that the lignan can subvert viral oncogene function resulting in stabilized p53 protein within treated HPV-containing tumor cells. The stabilized p53 is transcriptionally active as demonstrated by a luciferase reporter vector and induction of genes for Bax and PUMA proteins. Apoptosis is detected by annexin V binding to treated cells as analyzed by flow cytometry. Programmed cell death is confirmed by the induction of active caspases and TUNEL assay. Initiator caspase-9 is activated first, followed later by the effector caspase-3 enzyme. The stabilization and induced apoptosis are not observed within treated HPV-negative cervical tumor cells. Quantitative real time RT-PCR analysis of endogenous E6 gene transcription from the integrated HPV 16 promoter shows at least a fivefold repression of expression as compared to untreated cells. These results indicate that the loss of E6 protein in treated cells could be, in part, responsible for the stabilization of p53 within the lignan treated cells.
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PMID:A plant lignan, 3'-O-methyl-nordihydroguaiaretic acid, suppresses papillomavirus E6 protein function, stabilizes p53 protein, and induces apoptosis in cervical tumor cells. 1739 35

Persistent infection of hepatitis C virus (HCV) can lead to a high risk for hepatocellular carcinoma (HCC). HCV core protein plays important roles in HCV-related hepatocarcinogenesis, because mice carrying the core protein exhibit multicentric HCCs without hepatic inflammation and fibrosis. However, the precise mechanism of hepatocarcinogenesis in these transgenic mice remains unclear. To evaluate whether the core protein modulates hepatocyte proliferation and apoptosis in vivo, we examined these parameters in 9- and 22-month-old transgenic mice. Although the numbers of apoptotic hepatocytes and hepatic caspase 3 activities were similar between transgenic and nontransgenic mice, the numbers of proliferating hepatocytes and the levels of numerous proteins such as cyclin D1, cyclin-dependent kinase 4 and c-Myc, were markedly increased in an age-dependent manner in the transgenic mice. This increase was correlated with the activation of peroxisome proliferator-activated receptor alpha (PPARalpha). In these transgenic mice, spontaneous and persistent PPARalpha activation occurred heterogeneously, which was different from that observed in mice treated with clofibrate, a potent peroxisome proliferator. We further demonstrated that stabilization of PPARalpha through a possible interaction with HCV core protein and an increase in nonesterified fatty acids, which may serve as endogenous PPARalpha ligands, in hepatocyte nuclei contributed to the core protein-specific PPARalpha activation. In conclusion, these results offer the first suggestion that HCV core protein induces spontaneous, persistent, age-dependent and heterogeneous activation of PPARalpha in transgenic mice, which may contribute to the age-dependent and multicentric hepatocarcinogenesis mediated by the core protein.
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PMID:Hepatitis C virus core protein induces spontaneous and persistent activation of peroxisome proliferator-activated receptor alpha in transgenic mice: implications for HCV-associated hepatocarcinogenesis. 1776 15