Role of a Novel Nucleolar Protein in Regulation of E2F1 in Breast Cancer

摘要

Breast cancer is the second most common cancer in man and accounts for significant morbidity and mortality both from disease and treatment. Identifying molecular markers for survival and sensitivity to therapy is therefore important both for prognosis as well as elucidating mechanisms associated with tumorigenesis. A recent study has identified a novel protein, RRP1B, as being associated with reduced proliferation and metastasis and improved survival in breast cancer; however, the mechanism remains unclear. In this study, we identify RRP1B in a screen for specific targets of the DNA damage induced pro-apoptotic transcription factor E2F1. RRP1B is induced specifically by E2F1, but not the other non-apoptotic E2Fs, in a direct manner by promoter binding. Knockdown of RRP1B levels is associated with reduced sensitivity to DNA-damaging chemotherapeutic agents. RRP1B knockdown is associated with reduced transcription of selected other E2F1 targets, including the apoptosis effectors caspase-3 and -7. Finally, we show that RRP1B and E2F1 directly interact with each other in vitro and in vivo, and show that RRP1B and E2F1 bind selectively together on E2F1 transcriptional targets. All together, we identify a mechanism by which RRP1B can be associated with improved survival by affecting sensitivity to chemotherapy. We identify E2F1 as an important inducer of RRP1B, and furthermore identify a mechanism by which RRP1B can affect apoptosis directly through protein-protein interactions with E2F1 to control transcription of proapoptotic targets.