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Papers In Press, published online ahead of print November 21, 2002
J. Biol. Chem, 10.1074/jbc.M210327200
Submitted on October 9, 2002
Revised on November 20, 2002
Accepted on November 21, 2002

E2F mediates sustained G2 arrest and down-regulation of Stathmin and AIM-1 expression in response to genotoxic stress

Shirley Polager and Doron Ginsberg

Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100

Corresponding Author: doron.ginsberg{at}weizmann.ac.il

Abstract Exposure of cells to genotoxic agents results in activation of checkpoint pathways leading to cell cycle arrest. These arrest pathways allow repair of damaged DNA before its replication and segregation, thus preventing accumulation of mutations. The tumor suppressor RB is required for the G1/S checkpoint function. In addition, regulation of the G2 checkpoint by the tumor suppressor p53 is RB dependent. However, the molecular mechanism underlying the involvement of RB and its related proteins p107 and p130 in the G2 checkpoint is not fully understood. We show here that sustained G2/M arrest induced by the genotoxic agent doxorubicin is E2F-dependent and involves a decrease in expression of two mitotic regulators, Stathmin and AIM-1. Abrogation of E2F function by dominant negative E2F abolishes the doxorubicin-induced down-regulation of Stathmin and AIM-1 and leads to premature exit from G2. Expression of the E7 papilloma virus protein, which dissociates complexes containing E2F and RB family members, also prevents the down-regulation of these mitotic genes and leads to premature exit from G2 after genotoxic stress. Furthermore, genotoxic stress increases the levels of nuclear E2F-4 and p130 as well as their in vivo binding to the Stathmin promoter. Thus, functional complexes containing E2F and RB family members appear to be essential for repressing expression of critical mitotic regulators and maintaining the G2/M checkpoint.


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