Cell Growth & Differentiation, Vol 7, Issue 12 1599-1607, Copyright © 1996 by American Association of Cancer Research

ARTICLES

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

MS Sheikh, M Garcia, Q Zhan, Y Liu and AJ Fornace Jr
Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. mssheikh@box-m.nih.gov

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.

This article has been cited by other articles:

				E. R. Vickers, A. Kasza, I. A. Kurnaz, A. Seifert, L. A. H. Zeef, A. O'Donnell, A. Hayes, and A. D. Sharrocks Ternary Complex Factor-Serum Response Factor Complex-Regulated Gene Activity Is Required for Cellular Proliferation and Inhibition of Apoptotic Cell Death Mol. Cell. Biol., December 1, 2004; 24(23): 10340 - 10351. [Abstract] [Full Text] [PDF]

				L. Latella, J. Lukas, C. Simone, P. L. Puri, and J. Bartek Differentiation-Induced Radioresistance in Muscle Cells Mol. Cell. Biol., July 15, 2004; 24(14): 6350 - 6361. [Abstract] [Full Text] [PDF]

				A. Perez-Gomez, A. Garcia-Rodriguez, K. J. James, A. Ferrero-Gutierrez, A. Novelli, and M. T. Fernandez-Sanchez The Marine Toxin Dinophysistoxin-2 Induces Differential Apoptotic Death of Rat Cerebellar Neurons and Astrocytes Toxicol. Sci., July 1, 2004; 80(1): 74 - 82. [Abstract] [Full Text] [PDF]

				A.-K. R. Larsen, M. T. N. Moller, H. Blankson, H. R. Samari, L. Holden, and P. O. Seglen Naringin-sensitive Phosphorylation of Plectin, a Cytoskeletal Cross-linking Protein, in Isolated Rat Hepatocytes J. Biol. Chem., September 13, 2002; 277(38): 34826 - 34835. [Abstract] [Full Text] [PDF]

				D.J. Messner, P. Ao, A.B. Jagdale, and A.L. Boynton Abbreviated cell cycle progression induced by the serine/threonine protein phosphatase inhibitor okadaic acid at concentrations that promote neoplastic transformation Carcinogenesis, August 1, 2001; 22(8): 1163 - 1172. [Abstract] [Full Text] [PDF]

				L. Farhana, M. Boyanapalli, S.-H. R. Tschang, R.-J. Sun, C. K. A. Hsu, Y.-X. Zhang, J. A. Fontana, and A. K. Rishi Okadaic Acid-mediated Induction of the c-fos Gene in Estrogen Receptor-negative Human Breast Carcinoma Cells Utilized, in Part, Posttranscriptional Mechanisms Involving Adenosine-Uridine-rich Elements Cell Growth Differ., October 1, 2000; 11(10): 541 - 550. [Abstract] [Full Text]

				Y. Yan and M. C. Mumby Distinct Roles for PP1 and PP2A in Phosphorylation of the Retinoblastoma Protein. PP2A REGULATES THE ACTIVITIES OF G1 CYCLIN-DEPENDENT KINASES J. Biol. Chem., November 5, 1999; 274(45): 31917 - 31924. [Abstract] [Full Text] [PDF]

				D. Rajesh, K. Schell, and A. K. Verma Ras Mutation, Irrespective of Cell Type and p53 Status, Determines a Cell's Destiny to Undergo Apoptosis by Okadaic Acid, an Inhibitor of Protein Phosphatase 1 and 2A Mol. Pharmacol., September 1, 1999; 56(3): 515 - 525. [Abstract] [Full Text]

				M. Wu, R. E. Bellas, J. Shen, and G. E. Sonenshein Roles of the Tumor Suppressor p53 and the Cyclin-dependent Kinase Inhibitor p21WAF1/CIP1 in Receptor-mediated Apoptosis of WEHI 231 B Lymphoma Cells J. Exp. Med., May 18, 1998; 187(10): 1671 - 1679. [Abstract] [Full Text] [PDF]