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

Shirley Polager, Doron Ginsberg

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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 retinoblastoma (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.

Original languageEnglish
Pages (from-to)1443-1449
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number3
DOIs
StatePublished - 17 Jan 2003
Externally publishedYes

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