Yin Yang 1 protein negatively regulates high-density lipoprotein receptor gene transcription by disrupting binding of sterol regulatory element binding protein to the sterol regulatory element
W. Shea-eaton et al., Yin Yang 1 protein negatively regulates high-density lipoprotein receptor gene transcription by disrupting binding of sterol regulatory element binding protein to the sterol regulatory element, ENDOCRINOL, 142(1), 2001, pp. 49-58
Because the high-density lipoprotein receptor (HDL-R) is a key element in c
holesterol homeostasis and a potential therapeutic target for hypercholeste
rolemic drugs, an understanding of HDL-R regulation is essential. The stero
l regulatory element (SRE) binding protein-1a (SREBP-1a) was shown to posit
ively regulate HDL-R gene expression through two SREs. SREBP-1a requires th
e presence of a coactivator like simian-virus-40-protein-1 (Sp1) to promote
maximum activation of the HDL-R promoter. Negative regulatory factors are
also known to play a role in cholesterol homeostasis, and the ubiquitous Yi
n Yang-1 zinc finger transcription factor (YY1) has been shown to repress s
everal sterol-responsive gene promoters. A search of the rat HDL-R promoter
revealed two putative Wi binding sites (distal, -1329 to -1321; proximal,
-1211 to -1203). Upon removal of both Wi binding sites, Wi was unable to re
press HDL-R activation under basal (unstimulated) promoter conditions. Howe
ver, Wi was still an efficient transcriptional repressor for SREBP-1a-induc
ed activation. YY1 was able to attenuate the transcriptional synergy caused
by the combined actions of SREBP-1a and Spl. Two-hybrid studies confirmed
that Wi bound with high affinity to SREBP-1a, and mobility shift assays dem
onstrated that YY1 could disrupt SREBP-1a binding to both SREs. The molecul
ar consequence of YY1 intervention seems to override any positive interacti
ons between Sp-1 and SREBP-1a and results in the disruption of SREBP-1a bin
ding to the SREs in the HDL-R promoter.