Mechanism of E2F/p130 Mediated Repression and its Potential Tumor Suppressor Function in Breast Cancer

摘要

Transcriptional repression in quiescent cells is critical for the maintenance of cellular growth control. Previous work has shown the importance of E2F/Rb and E2F/pl3O complexes in mediating repression of genes that are involved in cell cycle progression, however, the mechanisms of action of these complexes remains unclear. The purpose of the work supported by this grant is to identify the mechanisms of pl3O mediated transcriptional repression. To this end we have established that pl3O recruits histone deacetylase as one mechanism of repression. Through a yeast two-hybrid screen, we have also found that the CtIP protein can interact with pl3O and mediate a histone deacetylase independent mechanism of transcriptional repression. This mechanism involves the recruitment of the CtBP protein, which we have found to he capable of inhibiting the CBP transcriptional coactivator. These findings are significant not only to cancers related to deregulated 52K activity but also to breast cancers involving mutations of ERCAl (Breast Cancer Susceptibility Gene l)as the BRCAl protein has been shown to interact functionally with CtIP.