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J. Biol. Chem., Vol. 275, Issue 48, 37829-37837, December 1, 2000

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Mediation of Nerve Growth Factor-driven Cell Cycle Arrest in PC12 Cells by p53
SIMULTANEOUS DIFFERENTIATION AND PROLIFERATION SUBSEQUENT TO p53 FUNCTIONAL INACTIVATION^*

Allison L. Hughes, Lakshmi Gollapudi^§, Todd L. Sladek^¶, and Kenneth E. Neet

From the Departments of  Biochemistry and Molecular Biology and ^¶ Microbiology and Immunology, Finch University of Health Sciences/Chicago Medical School, North Chicago, Illinois 60064

Upon stimulation with nerve growth factor (NGF), PC12 cells extend neurites and cease to proliferate by influencing cell cycle proteins. Previous studies have shown that neuritogenesis and a block at the G₁/S checkpoint correlate with the nuclear translocation of and an increase in the p53 tumor suppressor protein. This study was designed to determine if p53 plays a direct role in mediating NGF-driven G₁ arrest. A retroviral vector that overexpresses a temperature-sensitive p53 mutant protein (p53ts) was used to extinguish the function of endogenous p53 in PC12 cells in a dominant-negative manner at the nonpermissive temperature. NGF treatment led to transactivation of a p53 response element in a luciferase reporter construct in PC12 cells, whereas this response to NGF was absent in PC12(p53ts) cells at the nonpermissive temperature. With p53 functionally inactivated, NGF failed to activate growth arrest, as measured by bromodeoxyuridine incorporation, and also failed to induce p21/WAF1 expression, as measured by Western blotting. Since neurite outgrowth proceeded unharmed, 50% of the cells simultaneously demonstrated neurite morphology and were in S phase. Both PC12 cells expressing SV40 T antigen and PC12 cells treated with p53 antisense oligonucleotides continued through the cell cycle, confirming the dependence of the NGF growth arrest signal on a p53 pathway. Activation of Ras in a dexamethasone-inducible PC12 cell line (GSRas1) also caused p53 nuclear translocation and growth arrest. Therefore, wild-type p53 is indispensable in mediating the NGF antiproliferative signal through the Ras/MAPK pathway that regulates the cell cycle of PC12 cells.

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