DOMAINS OF TRANSCRIPTION FACTOR SP1 REQUIRED FOR SYNERGISTIC ACTIVATION WITH STEROL REGULATORY ELEMENT-BINDING PROTEIN-1 OF LOW-DENSITY-LIPOPROTEIN RECEPTOR PROMOTER
L. Yieh et al., DOMAINS OF TRANSCRIPTION FACTOR SP1 REQUIRED FOR SYNERGISTIC ACTIVATION WITH STEROL REGULATORY ELEMENT-BINDING PROTEIN-1 OF LOW-DENSITY-LIPOPROTEIN RECEPTOR PROMOTER, Proceedings of the National Academy of Sciences of the United Statesof America, 92(13), 1995, pp. 6102-6106
Feedback regulation of transcription from the low density lipoprotein
(LDL) receptor gene is fundamentally important in the maintenance of i
ntracellular sterol balance, The region of the LDL receptor promoter r
esponsible for normal sterol regulation contains adjacent binding site
s for the ubiquitous transcription factor Sp1 and the cholesterol-sens
itive sterol regulatory element-binding proteins (SREBPs), Interesting
ly, both are essential for normal sterol-mediated regulation of the pr
omoter, The cooperation by Sp1 and SREBP-1 occurs at two steps in the
activation process, SREBP-1 stimulates the binding of Sp1 to its adjac
ent recognition site in the promoter followed by enhanced stimulation
of transcription after both proteins are bound to DNA. In the present
report, we have defined the protein domains of Sp1 that are required f
or both synergistic DNA binding and transcriptional activation, The ma
jor activation domains of Sp1 that have previously been shown to be es
sential to activation of promoters containing multiple Sp1 sites are r
equired for activation of the LDL receptor promoter, Additionally, the
C domain is also crucial. This slightly acidic approximate to 120-ami
no acid region is not required for efficient synergistic activation by
multiple Sp1 sites or in combination with other recently characterize
d transcriptional regulators, We also show that Sp1 domain C is essent
ial for full, enhanced DNA binding by SREBP-1. Taken together with oth
er recent studies on the role of Sp1 in promoter activation, the curre
nt experiments suggest a unique combinatorial mechanism for promoter a
ctivation by two distinct transcription factors that are both essentia
l to intracellular cholesterol homeostasis.