The Bin1 tumor suppressor is a downstream mediator of E2F1-dependent apoptosis

Erica Lee Kinney, Purdue University

Abstract

The E2F1 transcription factor was originally identified as a cellular target that is induced by the adenovirus E1A oncoprotein. E2F1 transcriptionally regulates a number of genes that are associated with cell cycle progression. Paradoxically, several reports have suggested a role for E2F1 in tumor suppression. Different mechanisms have been attributed to the ability of E2F1 to promote apoptosis, which occur through p53-dependent and p53-independent pathways. p53 induction by E2F1 was widely accepted as an effective approach to suppress tumorigenesis. However, the discovery that many tumors lack functional p53 prompted investigation of other E2F1 pro-apoptotic target genes. Still, the precise downstream mechanisms of E2F1-induced apoptosis in the absence of p53 are not well-defined. The Bin1 tumor suppressor was originally identified as a c-Myc-interacting protein. Bin1 inhibits oncogenic Ras cellular co-transformation in cooperation with c-Myc or E1A. A c-Myc-binding-deficient form of Bin1 fails to inhibit c-Myc-dependent cell transformation but still suppresses E1A-dependent cellular transformation, suggesting that Bin1 is functionally involved in E1A-mediated signaling pathways. Ectopic Bin1 inhibits tumor growth of a variety of carcinoma cells and induces p53-independent apoptosis, but the upstream mechanisms which regulate Bin1 expression and function have yet to be determined. In this study, we propose a functional interplay between Bin1 and E2F1, wherein we hypothesize that Bin1 is required for E2F1-mediated apoptosis. We observed that attenuation of Bin1 expression blocks E2F1-dependent apoptosis in a manner that is distinct from p53 or the p53 homolog, p73. We furthermore demonstrate that Bin1 expression is enhanced by E2F1 through binding of E2F1 to E2F-consensus sites that lie within the Bin1 promoter. Conversely, E2F1 gene silencing using siRNA or germline mutations abrogate Bin1 expression. Lastly, in response to DNA damage, which stabilizes endogenous E2F1 via ATM/ATR dependent phosphorylation, Bin1 expression is upregulated in an E2F1-dependent manner and is required for DNA-damage induced apoptosis. Taken together, these results suggest that Bin1 is a novel transcriptional target of E2F1-dependent apoptosis.

Degree

Ph.D.

Advisors

Sakamuro, Purdue University.

Subject Area

Cellular biology

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