The sterol regulatory element-binding proteins (SREBPs)1 were first identified by two groups working independently on cholesterol metabolism (1, 2) and fat cell differentiation (3). Subsequent studies have demonstrated there are three major SREBP isoforms encoded by two different genes (4). These unique members of the basic helix-loop-helix leucine zipper (bHLHLZ) family of transcriptional regulatory proteins can be distinguished from other family members by two characteristics. The first is they are synthesized as precursors that are threaded into membranes of the endoplasmic reticulum and nuclear envelope in a hairpin orientation such that the amino and carboxyl tails both face the cytoplasm. The amino-terminal half of the precursor is clipped out of the membrane in two steps responding to regulatory cues that signal the need for increased cellular cholesterol (5). The released amino-terminal fragment, which contains the transcriptional activation and DNA binding domains, is targeted to the nucleus where it activates expression of SREBP target genes. The second distinguishing feature of the SREBPs is that they have a unique dual DNA binding specificity, which is discussed below.
Two of the three major isoforms are produced from the SREBP-1 gene, which contains two promoters (6). Transcription from each promoter produces an mRNA with a unique first exon that encodes one of the alternative amino termini referred to as 1a and 1c, respectively (Fig.1). These alternate exons are attached during mRNA splicing to a common second exon in the same reading frame, and therefore, the remaining protein coding information of both isoforms is identical. There is alternative mRNA splicing at the 3′-end as well (7), but this does not appear to be conserved in all mammalian species and its functional significance remains unclear (8).
Timothy F. Osborne. Sterol Regulatory Element-binding Proteins (SREBPs): Key Regulators of Nutritional Homeostasis and Insulin Action* Journal of Biological Chemistry 2000 October Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900.