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Molecular and Cellular Biology, September 2004, p. 8288-8300, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8288-8300.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Selective Coactivator Interactions in Gene Activation by SREBP-1a and -1c

Julia I. Toth,1 Shrimati Datta,1 Jyoti N. Athanikar,1,{dagger} Leonard P. Freedman,2 and Timothy F. Osborne1*

Department of Molecular Biology and Biochemistry, University of California, Irvine, California,1 Department of Molecular Endocrinology, Merck Research Laboratories, West Point, Pennsylvania2

Received 28 May 2004/ Accepted 11 June 2004

Requisite levels of intracellular cholesterol and fatty acids are maintained in part by the sterol regulatory element binding proteins (SREBPs). Three major SREBP isoforms exist; SREBP-1a and SREBP-1c are expressed from overlapping mRNAs, whereas SREBP-2 is encoded by a separate gene. The active forms of SREBP-1a and SREBP-1c differ only at their extreme N termini; SREBP-1c lacks 28 aa present in SREBP-1a and instead contains 4 unique aa of its own. While the SREBP-1a and -1c isoforms differentially activate transcription, the molecular basis of this difference is unknown. Here we define the differences between these proteins that confer the enhanced activity of SREBP-1a and demonstrate that this enhancement is a direct result of its avid binding to the coactivator CREB binding protein (CBP) and the mammalian mediator complex. While previous work determined that the C/H1 zinc finger and KIX domains of CBP bind to SREBP-1a, we provide evidence that the interaction with C/H1 is important for gene activation. We further show that the association between the activation domain of SREBP-1 and mediator is through aa 500 to 824 of DRIP150. Finally, we demonstrate the recruitment of mediator to an SREBP-responsive promoter in a sterol-dependent manner.

* Corresponding author. Mailing address: Molecular Biology and Biochemistry, 3244 McGaugh Hall, University of California, Irvine, Irvine, CA 92612-3900. E-mail: tfosborn{at}uci.edu.

{dagger} Present address: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-0618.

Molecular and Cellular Biology, September 2004, p. 8288-8300, Vol. 24, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.18.8288-8300.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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