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J. Biol. Chem., Vol. 280, Issue 5, 3338-3345, February 4, 2005

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Activation Domains from Both Monomers Contribute to Transcriptional Stimulation by Sterol Regulatory Element-binding Protein Dimers^*

Shrimati Datta and Timothy F. Osborne

From the Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900

Sterol regulatory element-binding proteins (SREBPs) are basic helix-loop-helix leucine zipper proteins that act as dimers to activate genes in lipid metabolism. Three SREBP isoforms, 1a, 1c, and 2, are expressed at varying levels in different tissues. Thus, homo- and heterodimers probably contribute to overall SREBP activity. No studies have directly evaluated the formation or activation properties of SREBP homo- and heterodimers. Studies with overexpressed SREBP monomers are inconclusive regarding the function of a particular SREBP dimer because of potential dimerization with endogenous proteins. To assess activation by a particular SREBP dimer, we fused DNA encoding individual monomers together via a predicted flexible polypeptide tether. Tethered SREBP dimers bound DNA equivalently to the monomeric proteins and were resistant to dominant negative SREBP-1 inhibition, confirming preferential formation of intramolecular dimers. Tethered SREBP-1a and -2 homodimers, similar to the monomeric forms, activated target genes more robustly than tethered SREBP-1c homodimers. A forced SREBP-1a/2 heterodimer had similar activity to the respective homodimers. However, SREBP-1c in a heterodimer with either SREBP-1a or -2 attenuated the activity relative to the SREBP-1a or -2 homodimers. These experiments provide some of the first data showing that the integrity of both activation domains in a dimeric transcription factor is required for maximal activity. In addition, the results support a model where changes in SREBP-1c protein expression that occur in response to insulin signaling and liver X receptor signaling would be predicted to increase or decrease overall SREBP activity in a tissue-specific fashion depending on the initial fractional contribution of SREBP-1c to total cellular levels of SREBP.

Received for publication, September 30, 2004 , and in revised form, November 8, 2004.

^* This work was supported in part by National Institutes of Health Grant HL48044. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Molecular Biology and Biochemistry, 3244 McGaugh Hall, University of California, Irvine, CA 92697-3900. Fax: 949-824-8551; E-mail: tfosborn{at}uci.edu.

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