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

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2004 Sep 2

PMID 15340088

Citations 58

Authors

Julia I Toth

Shrimati Datta

Jyoti N Athanikar

Leonard P Freedman

Timothy F Osborne

Affiliations

Soon will be listed here.

Abstract

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.

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References

Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B . A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 1996; 85(3):403-14. DOI: 10.1016/s0092-8674(00)81118-6. View

Lau J, Nusinzon I, Burakov D, Freedman L, Horvath C . Role of metazoan mediator proteins in interferon-responsive transcription. Mol Cell Biol. 2003; 23(2):620-8. PMC: 151539. DOI: 10.1128/MCB.23.2.620-628.2003. View

Sakai J, Duncan E, Rawson R, Hua X, Brown M, Goldstein J . Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. Cell. 1996; 85(7):1037-46. DOI: 10.1016/s0092-8674(00)81304-5. View

Fondell J, Ge H, Roeder R . Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. Proc Natl Acad Sci U S A. 1996; 93(16):8329-33. PMC: 38670. DOI: 10.1073/pnas.93.16.8329. View

Chakravarti D, LaMorte V, Nelson M, Nakajima T, Schulman I, Juguilon H . Role of CBP/P300 in nuclear receptor signalling. Nature. 1996; 383(6595):99-103. DOI: 10.1038/383099a0. View

Shimano H, Horton J, Hammer R, Shimomura I, Brown M, Goldstein J . Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest. 1996; 98(7):1575-84. PMC: 507590. DOI: 10.1172/JCI118951. View

Eckner R, Yao T, Oldread E, Livingston D . Interaction and functional collaboration of p300/CBP and bHLH proteins in muscle and B-cell differentiation. Genes Dev. 1996; 10(19):2478-90. DOI: 10.1101/gad.10.19.2478. View

Jackson S, Ericsson J, Metherall J, Edwards P . Role for sterol regulatory element binding protein in the regulation of farnesyl diphosphate synthase and in the control of cellular levels of cholesterol and triglyceride: evidence from sterol regulation-defective cells. J Lipid Res. 1996; 37(8):1712-21. View

Oliner J, Andresen J, Hansen S, Zhou S, Tjian R . SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein. Genes Dev. 1996; 10(22):2903-11. DOI: 10.1101/gad.10.22.2903. View

10.

Ericsson J, Jackson S, Kim J, Spiegelman B, Edwards P . Identification of glycerol-3-phosphate acyltransferase as an adipocyte determination and differentiation factor 1- and sterol regulatory element-binding protein-responsive gene. J Biol Chem. 1997; 272(11):7298-305. DOI: 10.1074/jbc.272.11.7298. View

11.

Shimomura I, Shimano H, Horton J, Goldstein J, Brown M . Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. J Clin Invest. 1997; 99(5):838-45. PMC: 507890. DOI: 10.1172/JCI119247. View

12.

Shimano H, Horton J, Shimomura I, Hammer R, Brown M, Goldstein J . Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest. 1997; 99(5):846-54. PMC: 507891. DOI: 10.1172/JCI119248. View

13.

Sundqvist A, Ericsson J . Transcription-dependent degradation controls the stability of the SREBP family of transcription factors. Proc Natl Acad Sci U S A. 2003; 100(24):13833-8. PMC: 283507. DOI: 10.1073/pnas.2335135100. View

14.

Lee S, Sekimoto T, Yamashita E, Nagoshi E, Nakagawa A, Imamoto N . The structure of importin-beta bound to SREBP-2: nuclear import of a transcription factor. Science. 2003; 302(5650):1571-5. DOI: 10.1126/science.1088372. View

15.

Dignam J, Lebovitz R, Roeder R . Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983; 11(5):1475-89. PMC: 325809. DOI: 10.1093/nar/11.5.1475. View

16.

Sakai A, Shimizu Y, Kondou S, Chibazakura T, Hishinuma F . Structure and molecular analysis of RGR1, a gene required for glucose repression of Saccharomyces cerevisiae. Mol Cell Biol. 1990; 10(8):4130-8. PMC: 360937. DOI: 10.1128/mcb.10.8.4130-4138.1990. View

17.

Gonzalez G, Menzel P, Leonard J, Fischer W, Montminy M . Characterization of motifs which are critical for activity of the cyclic AMP-responsive transcription factor CREB. Mol Cell Biol. 1991; 11(3):1306-12. PMC: 369401. DOI: 10.1128/mcb.11.3.1306-1312.1991. View

18.

Attardi L, Tjian R . Drosophila tissue-specific transcription factor NTF-1 contains a novel isoleucine-rich activation motif. Genes Dev. 1993; 7(7B):1341-53. DOI: 10.1101/gad.7.7b.1341. View

19.

Yokoyama C, Wang X, Briggs M, Admon A, Wu J, Hua X . SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell. 1993; 75(1):187-97. View

20.

Chrivia J, Kwok R, Lamb N, Hagiwara M, Montminy M, Goodman R . Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature. 1993; 365(6449):855-9. DOI: 10.1038/365855a0. View