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Abstract
Sterol regulatory element 1 (SRE-1), a decamer (5'-ATC-ACCCCAC-3') flanking the low
density lipoprotein (LDL) receptor gene, activates transcription in sterol-depleted
cells and is silenced by sterols. We report the cDNA cloning of human SREBP-1, a protein
that binds SRE-1, activates transcription, and thereby mediates the final regulatory
step in LDL metabolism. SREBP-1 contains a basic-helix-loop-helix-leucine zipper (bHLH-ZIP)
motif, but it differs from other bHLH-ZIP proteins in its larger size (1147 amino
acids) and target sequence. Instead of an inverted repeat (CANNTG), the target for
all known bHLH-ZIP proteins, SRE-1 contains a direct repeat of CAC. Overexpression
of SREBP-1 activates transcription of reporter genes containing SRE-1 in the absence
(15-fold) and presence (90-fold) of sterols, abolishing sterol regulation. We suggest
that SREBP-1 is regulated by an unknown factor that is overwhelmed when SREBP-1 is
overexpressed. Understanding the regulation of SREBP-1 may be crucial for understanding
the control of plasma cholesterol in humans.