Retinoic acid (RA) plays pleiotropic roles in cellular differentiation and animal development. RA responses are mediated by transcriptional activation by the retinoic acid receptor (RAR) and retinoid X receptor (RXR) in cooperation with various types of coregulators at RA-responsive gene promoters. Here, we identified CDK2-associated cullin (CAC1) as a novel type of RAR alpha coregulator that interacts with RAR alpha and inhibits its transcriptional activity. The CoRNR box of CAC1 is required for the binding to and inactivation of RAR alpha. In addition, CAC1 cooperates with histone deacetylases (HDACs) to suppress RAR alpha, probably by associating with HDAC. Finally, depletion of CAC1 increases RA-induced neuronal differentiation of P19 cells, a response accompanied by significant upregulation of the neuronal marker nestin. From these results, we suggest that CAC1 is a novel corepressor of RAR alpha that cooperates with HDACs and is involved in the regulation of RA-induced cellular differentiation. (C) 2012 Elsevier Inc. All rights reserved.