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SerpinB2 Protection of Retinoblastoma Protein from Calpain Enhances Tumor Cell Survival

¹ Center for Vascular and Inflammatory Diseases and the Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland and ² Immunovirology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia

Requests for reprints: Toni M. Antalis, University of Maryland School of Medicine, Biopark Building One, Room 220, 800 West Baltimore Street, Baltimore, MD 21201. Phone: 410-706-8222; Fax: 410-706-8121; E-mail: tantalis{at}som.umaryland.edu.

Key Words: Retinoblastoma protein • Plasminogen activator inhibitor type 2 • PAI-2 • SerpinB2 • apoptotic signal transduction

The tumor suppressor retinoblastoma protein (Rb) plays a pivotal role in the regulation of cell proliferation and sensitivity to apoptosis through binding to E2F transcription factors. Loss of Rb in response to genotoxic stress or inflammatory cytokines can enhance cell death, in part, by eliminating Rb-mediated repression of proapoptotic gene transcription. Here we show that calpain cleavage of Rb facilitates Rb loss by proteasome degradation and that this may occur during tumor necrosis factor –induced apoptosis. The cytoprotective, Rb-binding protein SerpinB2 (plasminogen activator inhibitor type 2) protects Rb from calpain cleavage, increasing Rb levels and enhancing cell survival. Chromatin immunoprecipitation assays show that the increased Rb levels selectively enhance Rb repression of proapoptotic gene transcription. This cytoprotective role of SerpinB2 is illustrated by reduced susceptibility of SerpinB2-deficient mice to multistage skin carcinogenesis, where Rb-dependent cell proliferation competes with apoptosis during initiation of papilloma development. These data identify SerpinB2 as a cell survival factor that modulates Rb repression of proapoptotic signal transduction and define a new posttranslational mechanism for selective regulation of the intracellular levels of Rb. [Cancer Res 2008;68(14):5648–57]