All ETDs from UAB

Advisory Committee Chair

Weei-Chin Lin

Advisory Committee Members

Louise T Chow

Jeffrey A Engler

Susan M Ruppert

Danny R Welch

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The E2F family of transcription factors are important regulators of cell proliferation, and are often dysregulated in cancers. One member of the E2F family, E2F1, also has the ability to induce apoptosis; therefore, uncovering how E2F1-induced apoptosis is controlled is of interest in understanding tumorigenesis. To this end, we identified RRP1B as a novel target specifically induced by E2F1. RRP1B expression is specifically upregulated by E2F1 overexpression, but not other E2F family members. RRP1B expression is correlated with E2F1 expression during the cell cycle, and is significantly induced after DNA damage. The minimal RRP1B promoter region responsive to E2F1 was identified. Finally, E2F1, but not other E2F family members, was shown to bind endogenous RRP1B promoters through chromatin immunoprecipitation assays. To determine the function of RRP1B in regulation of E2F1-induced apoptosis, we then constructed cell lines stably transfected with siRNAs against RRP1B. Knockdown of RRP1B inhibited apoptosis induced by genotoxic stimuli. Knockdown of RRP1B was able to inhibit the expression of selective E2F1 targets, including caspase-3 and -7 which are involved in apoptosis. We also determined that RRP1B and E2F1 interact both in vitro and in vivo, and also showed that RRP1B specifically bound to the promoters of E2F1 targets that were selectively affected by RRP1B knockdown. Together, this data suggests that E2F1-induced apoptosis is mediated in part by induction of RRP1B, interaction between E2F1 and RRP1B, and binding to the promoters of selective proapoptotic E2F1 targets.

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