1. ¹International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Shanghai 200438, China
2. ²Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China
3. ³State Key Laboratory for Oncogenes and Related Genes, Cancer Institute of Shanghai Jiao Tong University, Shanghai 200032, China

Correspondence: Hong Yang Wang, Tel: +86-21-25070856; Fax: +86-21-65566851 E-mail: hywangk@vip.sina.com

^*These three authors contributed equally to this work.

Received 15 October 2007; Accepted 19 October 2007.

Abstract

p28^GANK (also known as PSMD10, p28 and gankyrin) is an ankyrin repeat anti-apoptotic oncoprotein that is commonly overexpressed in hepatocellular carcinomas and increases the degradation of p53 and Rb. NF-B (nuclear factor-B) is known to be sequestered in the cytoplasm by IB (inhibitor of NF-B) proteins ^{1, 2}, but much less is known about the cytoplasmic retention of NF-B by other cellular proteins. Here we show that p28^GANK inhibits NF-B activity. As a nuclear-cytoplasmic shuttling protein, p28^GANK directly binds to NF-B/RelA and exports RelA from nucleus through a chromosomal region maintenance-1 (CRM-1) dependent pathway, which results in the cytoplasmic retention of NF-B/RelA. We demonstrate that all the ankyrin repeats of p28^GANK are required for the interaction with RelA and that the N terminus of p28^GANK, which contains the nuclear export sequence (NES), is responsible for suppressing NF-B/RelA nuclear translocation. These results suggest that overexpression of p28^GANK prevents the nuclear localization and inhibits the activity of NF-B/RelA.