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PGC-1-Related Coactivator: Immediate Early Expression and Characterization of a CREB/NRF-1 Binding Domain Associated with Cytochrome c Promoter Occupancy and Respiratory Growth

Department of Cell and Molecular Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611,¹ Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95100 Catania, Italy²

Received 4 April 2006/ Returned for modification 25 May 2006/ Accepted 31 July 2006

PGC-1-related coactivator (PRC) was initially characterized as a transcriptional coactivator that shares structural and functional features with PGC-1. Both coactivators interact with nuclear respiratory factor 1 (NRF-1) and activate NRF-1 target genes required for respiratory chain expression. Here, we establish that PRC belongs to the class of immediate early genes that are rapidly induced in the transition from quiescence to proliferative growth. As observed for other members of this class, the rapid serum induction of PRC mRNA does not require de novo protein synthesis and inhibition of protein synthesis stabilizes PRC mRNA, leading to its superinduction. Previous work indicated that PRC activation of cytochrome c expression occurs through cis-acting elements that bind both NRF-1 and CREB. Here, we demonstrate that, like NRF-1, CREB binds PRC in vitro and exists in a complex with PRC in cell extracts. Both CREB and NRF-1 bind the same sites on PRC, and the interaction with CREB requires the CREB b-Zip DNA binding domain. Moreover, a CREB/NRF-1 interaction domain on PRC is required for its trans activation of the cytochrome c promoter and a PRC subfragment containing this domain inhibits respiratory growth on galactose when expressed in trans from a lentivirus vector. Finally, PRC associates with the cytochrome c promoter in vivo and its occupancy of the promoter is markedly elevated in response to serum induction of quiescent fibroblasts. The results establish that PRC is an immediate early gene product that can target key transcription factors as an early event in the program of cellular proliferation.

Published ahead of print on 14 August 2006.

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