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J. Biol. Chem., Vol. 279, Issue 15, 15604-15614, April 9, 2004

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Nerve Growth Factor Withdrawal-mediated Apoptosis in Naïve and Differentiated PC12 Cells through p53/Caspase-3-dependent and -independent Pathways^*

Houman Vaghefi, Allison L. Hughes, and Kenneth E. Neet¶

From the Department of Biochemistry and Molecular Biology, The Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago, Illinois 60064

Programmed cell death is regulated in response to a variety of stimuli, including the tumor suppressor protein p53, that can mediate cell cycle arrest through p21/Waf1 and apoptosis through the Bcl-2/Bax equilibrium and caspases. Neuronal cell apoptosis has been reported to require p53, whereas other data suggest that neuronal cell death may be independent of p53. Comparison of wild type PC12 to a temperature-sensitive PC12 cell line that depresses the normal function of p53 has permitted investigation of the importance of p53 in a variety of cell functions. This study examined the role of p53 in trophic factor withdrawal-mediated apoptosis in both naïve and differentiated PC12 cells. Our data show that as PC12 cells differentiate they are more poised to undergo apoptosis than their undifferentiated counterparts. Survival assays with XTT (sodium 3'-1-(phenylaminocarbonyl)-3,4-tetrazolium-bis(4-methoxy-6-nitro)benzene sulfonic acid) and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) demonstrated that lack of p53 is initially protective against apoptosis. The window of protection is about 20 h for naïve and 36 h for differentiated cells. Apoptosis involved caspases 3, 6, and 9. However, caspase 3 activation was absent in cells lacking p53, concomitant with the delayed apoptosis. When the expression of caspase 3 was silenced with interference RNA, wild type PC12 cells revealed a morphology and biochemistry similar to PC12[p53ts] cells, indicating that caspase 3 accounts for the observed delay in apoptosis in p53 dysfunction. These results suggest that p53 is important, but not essential, in factor withdrawal-mediated apoptosis. Parallel pathways of caspase-mediated apoptosis are activated later in the absence of functional p53.

Received for publication, October 20, 2003 , and in revised form, January 5, 2004.

^* This work was supported in part by a grant from the USPHS, National Institutes of Health Grant NS24380 (to K. E. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Submitted as partial fulfillment of the requirements for the degree of Doctor of Philosophy, Finch University of Health Sciences, The Chicago Medical School, 2002.

Current address: Dept. of Dermatology, Wayne State University, Detroit, MI 48201.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, The Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd., North Chicago, IL 60064. Tel.: 847-578-3220; Fax: 847-578-3240; E-mail: Kenneth.Neet{at}rosalindfranklin.edu.

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