Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report here that p21WAF1/CIP1, an inhibitor of cyclin kinases, underwent proteolytic processing into a smaller fragment, p14, in the early stage of apoptosis in SK-HEP-1 cells. Apoptosis was induced by either staurosporine or ginsenoside Rh2, a ginseng saponin with a dammarane skeleton. Proteolytic processing was the result of caspase-3 activity, which accompanied the early changes in cell morphology and DNA fragmentation. p21WAF1/CIP1 translated in vitro was cleaved into a p14 fragment when incubated with cell extracts obtained from either ginsenoside Rh2-treated or staurosporine-treated cells. Cleavage was equally inhibited in both cases by adding Ac-DEVD-CHO, a specific caspase-3 inhibitor, but not by Ac-YVAD-CHO, a specific caspase-1 inhibitor. Similarly, p21WAF1/CIP1 was efficiently cleaved by recombinant caspase-3, overexpressed in Escherichia coli. Moreover, the endogenous p21WAF1/CIP1 of untreated cell extracts was also cleaved by recombinant caspase 3, as measured by immunoblotting. Mutation analysis allowed identification of two caspase-3 cleavage sites, DHVD112/L and SMTD149/F, which are located within or near the interaction domains for cyclins, Cdks, and proliferating cell nuclear antigen (PCNA). Taken together, these results show that ginsenoside Rh2 and staurosporine increase caspase-3 activity, which in turn directly cleaves p21WAF1/CIP1 during the early stages of apoptosis. We propose that proteolytic cleavage of p21WAF1/CIP1 is a functionally relevant event that allows release of the cyclin/Cdk complex from the p21WAF1/CIP1 inhibitor, resulting in the elevated levels of cyclin/Cdk kinase activity seen in the earlier stage of apoptosis.
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PMID:Caspase 3 specifically cleaves p21WAF1/CIP1 in the earlier stage of apoptosis in SK-HEP-1 human hepatoma cells. 979 25

The glycoprotein hormone, human chorionic gonadotropin (hCG) inhibits mammary tumorigenesis through induction of differentiation, and inhibits the proliferation of human breast epithelial cells (HBEC) in vitro. The present study was designed to determine whether the inhibitory effects of hCG was associated with the modulation of apoptotic gene expression. MCF-10F, a normal immortalized HBEC, BP1-E, a benzo(a)pyrene (BP) transformed cell line, and the urothelial cell line T24, were treated with 100 IU/ml of a commercially available preparation of hCG. Cell growth analysis and RNA extraction for determination of apoptotic gene expression were performed at 24 and 120 hrs of hCG treatment. Both hCG-treated and control cells grew at similar rates for the first 24 hours. A significant reduction in the number of viable MCF-10F and BP1-E cells occurred by 120 hours of treatment, whereas the number of both hCG treated and control T24 cells were similar. Northern blot analysis revealed that the 24 hour-hCG treatment induced an elevation in the expression of the apoptotic genes TRPM2, ICE, TGF-beta, p53, bax, and p21WAF1/CIP1 in MCF-10F cells. By 120 hours of treatment MCF-10F cells maintained the same level of gene expression observed at 24 hours, except for a reduction in c-myc and bax. Control cells exhibited an elevation in the expression of TRPM2, TGF-beta, p53, bax, and p21WAF1/CIP1, whose levels became similar to those observed in hCG-treated cells. The 24 hour-treated BP1-E cells showed activation of ICE, bax and p21WAF1/CIP1. However, TRPM2 expression was moderately activated. By 120 hours TRPM2, ICE, TGF-beta, c-myc and p21WAF1/CIP1 were elevated in both treated and control cells except bax which was slightly down-regulated. The levels of bc12 were significantly decreased by hCG treatment. Gene expression was not modified by hCG treatment in T24 cells. Our findings suggest that hCG induced an acceleration in the expression of apoptotic genes, which became evident before detection of cell growth inhibition. Gene activation differed among immortalized, and chemically transformed cells, suggesting that hCG might utilize both p53 dependent and p53 independent pathways for inhibiting cell cycle progression. The importance of these findings lies in the potential use of agents like hCG for the chemoprevention and chemotherapy of breast cancer.
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PMID:Growth inhibition and activation of apoptotic gene expression by human chorionic gonadotropin in human breast epithelial cells. 989 38

Butyric acid, an extracellular metabolite from periodontopathic bacteria, induces apoptosis in murine thymocytes, splenic T-cells, and human Jurkat T-cells. The present study examines the contributions of apoptosis-related proteins (Bcl-2, Bcl-XL, Bax, and p21WAF1/CIP1) in the regulation of T-cell death induced by butyric acid, using p53 knock-out (p53-/-) and wild-type (p53+/+) mice. The results of a DNA fragmentation assay indicated that thymocytes, splenic T-cells, and B-cells from p53-/- mice were susceptible to butyric-acid-induced apoptosis to a degree similar to those from p53+/+ mice. Moreover, butyric acid significantly induced apoptosis in lymphocytes from both p53+/+ and p53-/- mice in a concentration- and time-dependent fashion. Experiments with fractionated subpopulations of splenic T-cells revealed that DNA fragmentation was equally observed in CD4+ and CD8+ splenic T-cells from both p53+/+ and p53-/- lymphocytes. Activation of caspase-3, caspase-6, and caspase-8, but not of caspase-1, in butyric-acid-induced T-cell apoptosis occurred regardless of the presence of p53. Western blotting analysis of splenic T-cells showed that butyric acid treatment decreased Bcl-2 and Bcl-XL expressions in p53+/+ and p53-/- cells. Splenic T-cells had barely detectable Bax and p21WAF1/CIP1, regardless of whether butyric acid and/or p53 was present. These results suggest that butyric-acid-mediated apoptosis of murine T-cells takes place via a pathway that is independent of p53, and is followed by the p53-regulated proteins Bax and p21WAF1/CIP1, which lower the levels of the apoptosis antagonists Bcl-2 and Bcl-XL in cells.
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PMID:Butyric-acid-induced apoptosis in murine thymocytes and splenic T- and B-cells occurs in the absence of p53. 1120 Oct 44