Differential Transcriptional Activation by Two Sterol Regulatory Element Binding Protein-1 Isoforms, -1a and -1c
Jyoti N. Athanikar and Timothy F. Osborne.
Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, CA, USA
Requisite levels of intracellular cholesterol and fatty acids are maintained by a family of transcription factors known as sterol regulatory element binding proteins (SREBPs). SREBPs are synthesized as precursor molecules that are normally sequestered in the membrane of the endoplasmic reticulum. When cellular sterol levels decrease the mature N-terminal half is released by a two step proteolytic process which translocates to the nucleus. Once inside the nucleus, they activate genes involved in the uptake of cholesterol and biosynthesis of cholesterol and fatty acids. There are three major isoforms of SREBPs; SREBP-1a and SREBP-1c are expressed from alternative mRNAs encoded from the same gene and SREBP-2 is produced from a separate gene as a singular transcript. Recent studies have documented functional differences between the three SREBP isoforms although the precise physiologic roles for each have not yet been firmly established. The mature forms of SREBP-1a and SREBP-1c only differ at their extreme N-termini, SREBP-1c lacks 29 amino acids present in -1a and contains five unique amino acids. Comparison of SREBP-1a and -1c in both animals and cultured cells revealed that SREBP-1a is a more potent transcriptional activator than SREBP-1c. Our present studies reveal that although SREBP-1c is a weak activator, it did not attenuate the activity of SREBP-1a when they were both expressed together in the same cells. We show that the five unique amino acids present in SREBP-1c are important for the activation observed by -1c and the removal of these amino acids allows SREBP-1c to behave as a dominant negative inhibitor of SREBP-1a. We also demonstrate that the weak activation potential of SREBP-1c is due to its inefficient interaction with the co-activator CREB binding protein (CBP) which is required for efficient activation by SREBP-1a. Finally we show that SREBP-1a and -1c may be differentially regulated by the MAP kinase signaling pathway.