Document Detail


Cell cycle-independent regulation of p21Waf1/Cip1 and retinoblastoma protein during okadaic acid-induced apoptosis is coupled with induction of Bax protein in human breast carcinoma cells.
MedLine Citation:
PMID:  8959327     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Okadaic acid (OA) is a serine/threonine protein phosphatase inhibitor and has been shown to induce apoptosis in a number of different tumor cell lines, including human breast carcinoma (HBC) cells. The molecular basis of OA-induced apoptosis remains to be investigated. Here, we demonstrate that the OA concentration that inhibits only protein phosphatase 1 and 2A was sufficient to induce apoptosis in HBC cells. In MCF-7 cells, the OA-induced apoptosis was coupled with the overexpression of endogenous p53, p21Waf1/Cip1, and Bax proteins, whereas the Rb protein levels were decreased. OA also induced apoptosis and concomitantly enhanced the p21Waf1/Cip1 and Bex levels in human papilloma virus protein E6-transfected variants of MCF-7 cells, in which p53 function had been disrupted. OA, by contrast, had no effect on the levels or the subcellular localization of Gadd45 and Bcl2 proteins in either wild-type of E6-transfected MCF-7 cells. Bcl-xL, Bcl-xS, and Bak levels were also unchanged after OA treatment in both cell types. OA-induced apoptosis and its effect on the expression of the above molecular markers occurred in the absence of any detectable changes in the cell cycle phase distribution. On the basis of our findings, we conclude the following: (a) OA-induced apoptosis in HBC cells occurs independently of cell cycle arrest; (b) the wild-type p53 function is not an absolute prerequisite for OA-induced cell death; and (c) OA-induced apoptosis is associated with up-regulation of endogenous p21Waf1/Cip1 and Bax protein levels.
Authors:
M S Sheikh; M Garcia; Q Zhan; Y Liu; A J Fornace
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research     Volume:  7     ISSN:  1044-9523     ISO Abbreviation:  Cell Growth Differ.     Publication Date:  1996 Dec 
Date Detail:
Created Date:  1997-03-07     Completed Date:  1997-03-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9100024     Medline TA:  Cell Growth Differ     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1599-607     Citation Subset:  IM    
Affiliation:
Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. mssheikh@box-m.nih.gov
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects,  physiology*
Biological Markers
Blotting, Western
Breast Neoplasms
Cell Cycle / physiology
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / analysis,  metabolism*
DNA Damage / physiology
Down-Regulation / drug effects
Enzyme Inhibitors / analysis,  metabolism*
Female
Gene Expression Regulation, Neoplastic / physiology
Humans
Immunohistochemistry
Intracellular Signaling Peptides and Proteins
Okadaic Acid / pharmacology*
Phosphoric Monoester Hydrolases / antagonists & inhibitors
Proteins / analysis,  metabolism
Proto-Oncogene Proteins / analysis,  genetics*
Proto-Oncogene Proteins c-bcl-2 / metabolism
Retinoblastoma Protein / metabolism*
Tumor Cells, Cultured / cytology,  drug effects,  enzymology
Tumor Suppressor Protein p53 / analysis,  drug effects,  metabolism
bcl-2-Associated X Protein
Chemical
Reg. No./Substance:
0/BAX protein, human; 0/Biological Markers; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Enzyme Inhibitors; 0/GADD45 protein; 0/Intracellular Signaling Peptides and Proteins; 0/Proteins; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Retinoblastoma Protein; 0/Tumor Suppressor Protein p53; 0/bcl-2-Associated X Protein; 78111-17-8/Okadaic Acid; EC 3.1.3.-/Phosphoric Monoester Hydrolases

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