TY - JOUR T1 - DNA Damage Induces a Novel p53-Survivin Signaling Pathway Regulating Cell Cycle and Apoptosis in Acute Lymphoblastic Leukemia Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 124 LP - 131 DO - 10.1124/jpet.102.037192 VL - 303 IS - 1 AU - Muxiang Zhou AU - Lubing Gu AU - Fengzhi Li AU - Yerun Zhu AU - William G. Woods AU - Harry W. Findley Y1 - 2002/10/01 UR - http://jpet.aspetjournals.org/content/303/1/124.abstract N2 - 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-G1compartment). 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. The American Society for Pharmacology and Experimental Therapeutics ER -