COOPERATION BY STEROL REGULATORY ELEMENT-BINDING PROTEIN AND SP1 IN STEROL REGULATION OF LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE

Regulation of the low density lipoprotein (LDL) receptor promoter by c holesterol requires a well defined sterol regulatory site and an adjac ent binding site for the universal transcription factor Sp1. These ele ments are located in repeats 2 and 3 of the wild type promoter, respec tively, The experiments reported here demon strate that Sp1 participat es in sterol regulation of the LDL receptor in an orientation-specific fashion. We pre sent data which suggest that sterol regulatory elemen t binding protein (SREBP) increases the binding of Sp1 to the adjacent repeat 3 sequence. We also demonstrate that SREBP and Sp1 synergistic ally activate expression from the LDL receptor promoter inside the cel l by cotransfecting expression vectors encoding each protein into Dros ophila tissue culture cells that are devoid of endogenous Sp1. In addi tion, other transcription factor sites were unable to substitute for S p1 in sterol regulation when placed next to the SREBP-binding site, Th ese studies together with recent data from others provide the basis of a working model for sterol regulation of the LDL receptor promoter, T he presence of Sp1 sites in several other regulated promoters suggests that this universal transcription factor has been recruited to partic ipate in many regulatory responses possibly by a similar mechanism.