Estrogen receptor-related receptor gamma (ERR gamma) is a member of the nuclear receptor family of transcriptional activators. To date, the target genes and physiological functions of ERR gamma are not well understood. In the current study, we identify that Plk2 is a novel target of ERR gamma. Northern blot analysis showed that overexpression of ERR gamma induced P1k2 expression in cancer cell lines. ERR gamma activated the P1k2 gene promoter, and deletion and mutational analysis of the Plk2 promoter revealed that the ERR gamma-response region is located between nucleotides (nt) -2327 and -2229 and -441 and -432 (relative to the transcriptional start site at +1). Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis demonstrated that ERR gamma binds directly to the Plk2 promoter. Overexpression of ERR gamma in the presence of the mitotic inhibitor nocodazole significantly decreased apoptosis, and induced S-phase cell cycle progression through the induction of Plk2 expression. Taken together, these results demonstrated that P1k2 is a novel target of ERR gamma, and suggest that this interaction is crucial for cancer cell proliferation. (c) 2007 Elsevier Inc. All rights reserved.