XLG alpha(olf) is an extra large transcriptional variant of the heterotrimeric G protein, G alpha(olf), which we previously reported to be localized in the Golgi apparatus and interacted with Rab3A and Rab8A through its N-terminal region. However, many physiological functions of XLG alpha(olf) remain to be elucidated. In this study, performance of yeast two-hybrid screening with XLG alpha(olf) allowed isolation of COP9 signalosome subunit 5 (CSN5), known to regulate the p27(Kip1) protein level through a proteasome dependent pathway. Co-immunoprecipitation experiments followed. by Western blotting also showed association of CSN5 with XLG alpha(olf) linked to down-regulation of p27(Kip1). Gene silencing of endogenous CSN5 by siRNA attenuated the XLG alpha(olf)-mediated down-regulation, which was also demonstrated to require CDK2. Both knock down of CDK2 and the treatment with a CDK2 inhibitor reversed the reduction of p27(Kip1) due to XLG alpha(olf). Our findings provide important clues to understanding physiological functions of XLG alpha(olf). (C) 2011 Elsevier Inc. All rights reserved.