Co-stimulation of promoter for low density lipoprotein receptor gene by sterol regulatory element-binding protein and Sp1 is specifically disrupted by the yin yang 1 protein

Sterol regulation of gene expression in mammalian cells is mediated by an i nteraction between the cholesterol-sensitive sterol regulatory element-bind ing proteins (SREBPs) and promoter-specific but generic co-regulatory trans cription factors such as Spl and NF-Y/CBF, Thus, sterol-regulated promoters that require different co-regulatory factors could be regulated independen tly through targeting the specific interaction between the SREBPs and the i ndividual co-regulatory proteins. In the present studies we demonstrate tha t transiently expressed yin yang 1 protein (YY1) inhibits the SREBP-mediate d activation of the low density lipoprotein (LDL) receptor in a sensitive a nd dose dependent manner. The inhibition is independent of YY1 binding dire ctly to the LDL receptor promoter, and we show that the same region of YY1 that interacts in solution with Spl also interacts with SREBP. Furthermore, other SREBP-regulated genes that are not co-regulated by Spl are either no t affected at all or are not as sensitive to the repression. Thus, the spec ific interaction that occurs between SREBPs and Spl to stimulate the LDL re ceptor promoter is a specific target for inhibition by the YY1 protein, and we provide evidence that the mechanism can be at least partially explained by the ability of YY1 to inhibit the interaction between SREBP and Spl in solution in vitro, The LDL receptor is the key gene of cholesterol uptake, and the rate-controlling genes of cholesterol synthesis are stimulated by t he concerted action of SREBPs along with coregulators that are distinct fro m Spl, Therefore, repression of gene expression through specifically target ing the interaction between SREBP and Spl would provide a molecular mechani sm to explain how cholesterol uptake can be regulated independently from ch olesterol biosynthesis in mammalian cells.