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Vol. 303, Issue 1, 124-131, October 2002

DNA Damage Induces a Novel p53-Survivin Signaling Pathway Regulating Cell Cycle and Apoptosis in Acute Lymphoblastic Leukemia Cells

Muxiang Zhou, Lubing Gu, Fengzhi Li, Yerun Zhu, William G. Woods and Harry W. Findley

Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia (M.Z., L.B., Y.Z., W.G.W., H.W.F.), and Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York (F.L.)

Survivin is a novel member of the inhibitor of apoptosis protein (IAP) family. Here we report that the chemotherapeutic drug doxorubicin, a DNA-damaging agent, activates a p53-survivin signaling pathway inducing cell cycle arrest and apoptosis in childhood acute lymphoblastic leukemia (ALL). Treatment of wild-type (wt) p53 ALL cells (EU-3 cell line) with doxorubicin caused accumulation of p53, resulting in dramatic down-regulation of survivin, depletion of cells in G2/M, and apoptosis (increased sub-G1 compartment). In contrast, doxorubicin treatment of mutant (mut) p53 cells (EU-6/ALL line) up-regulated survivin and induced G2/M arrest without inducing apoptosis. However, treating EU-6 with anti-survivin antisense resensitized these cells to doxorubicin, resulting in apoptosis. With a p53-null cell line (EU-4), although doxorubicin treatment arrested cells in G2/M, survivin expression was unchanged, and cells underwent only limited apoptosis. However, re-expression of wt-p53 in EU-4 cells could restore the doxorubicin-p53-survivin pathway, resulting in significantly decreased survivin expression and increased apoptosis in these cells after doxorubicin treatment. Following cotransfection of p53-null EU-4 cells with survivin promoter-luciferase constructs and either wt-p53 or different mut-p53 expression vectors, wt-p53 inhibited survivin promoter activity; p53-mediated inhibition could be abrogated by overexpression of murine double minute2 (MDM2) protein. Together, these studies define a novel p53-survivin signaling pathway activated by DNA damage that results in down-regulation of survivin, cell cycle arrest, and apoptosis. Furthermore, our data indicate that loss of wt-p53 function in tumor cells may contribute to up-regulation of survivin and resistance to DNA-damaging agents.

0022-3565/02/3031-0124$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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