Nucleic Acids Research, Vol 25, Issue 20 4132-4138, Copyright © 1997 by Oxford University Press
P Dhawan, R Chang and KD Mehta
Low density lipoprotein (LDL) receptor gene is regulated at the
transcriptional level by the intracellular level of sterols in animal
cells. We have recently identified a 20 bp long region (-145 to -126),
designated Footprint 1 (FP1), participating in maximal expression of the
human LDL receptor gene in the absence of sterols in HepG2 cells [Mehta, K.
D., Chang, R., Underwood, J., Wise, J. and Kumar, A. (1996) J. Biol. Chem
., 271, 33616-33622]. To determine the minimal FP1 sequence and to define
the critical nucleotides required for function, a series of single
nucleotide substitutions were introduced in the FP1 region. Twenty-three
independent mutations were analyzed by transfection into HepG2 cells. These
studies localize the regulatory region to 14 bp and demonstrate the
requirement for essential guanine nucleotides at positions -135 and -136
for FP1 function. Furthermore, transfection studies suggest that the
FP1-dependent increase in reporter gene expression is possibly mediated
through interaction with the sterol-regulatory element. UV cross-linking
and Southwestern blot analysis identified FP1-binding factors of
approximately 50 and 125 kDa, which we have denoted p50 and p125. Mutations
of the critical guanine residues (-135/-136) decreased the formation of the
specific protein-DNA complex with the FP1 sequence and abolished its
binding to the p125. We conclude that direct interaction of the p125 factor
with these nucleotides of the FP1 element potentially contributes to FP1-
dependent induction of LDL receptor gene expression.
ARTICLES
Identification of essential nucleotides of the FP1 element responsible for enhancement of low density lipoprotein receptor gene transcription
Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA.
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