SerpinB2 protection of retinoblastoma protein from calpain enhances tumor cell survival

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 eliminatin...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2008-07, Vol.68 (14), p.5648-5657
Main Authors: Tonnetti, Laura, Netzel-Arnett, Sarah, Darnell, Grant A, Hayes, Tamara, Buzza, Marguerite S, Anglin, Ian E, Suhrbier, Andreas, Antalis, Toni M
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Calpain - metabolism
Cell Survival
Fibroblasts - metabolism
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
HeLa Cells
Humans
Jurkat Cells
Mice
Plasminogen Activator Inhibitor 2 - genetics
Plasminogen Activator Inhibitor 2 - metabolism
Plasminogen Activator Inhibitor 2 - physiology
Retinoblastoma Protein - metabolism
Signal Transduction
Skin Neoplasms - metabolism
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Summary: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 alpha-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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-07-5850