PGC-l-related coactivator, a novel, serum-inducible coactivator of nuclearrespiratory factor 1-dependent transcription in mammalian cells

he thermogenic peroxisome proliferator-activated receptor gamma (PPAR-gamma ) coactivator 1 (PGC-1) has previously been shown to activate mitochondrial biogenesis in part through a direct interaction with nuclear respiratory f actor 1 (NRF-1), In order to identify related coactivators that act through NRF-1, we searched the databases for sequences with similarities to PGC-1, Here, we describe the first characterization of a 177-kDa transcriptional coactivator, designated PGC-l-related coactivator (PRC), PRC is ubiquitousl y expressed in murine and human tissues and cell lines; but unlike PGC-1, P RC was not dramatically up-regulated during thermogenesis in brown fat. How ever, its expression was down-regulated in quiescent BALB/3T3 cells and was rapidly induced by reintroduction of serum, conditions where PGC-1 was not detected. PRC activated NRF-1-dependent promoters in a manner similar to t hat observed for PGC-1, Moreover, NRF-1 was immunoprecipitated from cell ex tracts by antibodies directed against PRC, and both proteins were colocaliz ed to the nucleoplasm by confocal laser scanning microscopy. PRC interacts in vitro with the NRF-1 DNA binding domain through two distinct recognition motifs that are separated by an unstructured proline-rich region. PRC also contains a potent transcriptional activation domain in its amino terminus adjacent to an LXXLL motif, The spatial arrangement of these functional dom ains coincides with those found in PGC-1, supporting the conclusion that PR C and PGC-1 are structurally and functionally related. We conclude that PRC is a functional relative of PGC-I that operates through NRF-1 and possibly other activators in response to proliferative signals.