Physical and functional interactions between liver X receptor/retinoid X receptor and Sp1 modulate the transcriptional induction of the human ATP binding cassette transporter A1 gene by oxysterols and retinoids

被引:44
作者
Thymiakou, Efstathia
Zannis, Vassilis I.
Kardassis, Dimitris [1 ]
机构
[1] Univ Crete, Sch Med, Dept Basic Sci, Biochem Lab, Iraklion 71110, Greece
[2] Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Iraklion 71110, Greece
[3] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Dept Med Biochem, Boston, MA 02118 USA
关键词
D O I
10.1021/bi700994m
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The lipid transporter ATP binding cassette transporter A1 (ABCA1) promotes the efflux of cellular phospholipids and cholesterol to lipid-free apolipoprotein A-I and thus initiates the biogenesis of high-density lipoprotein (HDL). The expression of the ABCAl gene is controlled, coordinately with other genes of HDL metabolism, by liver X receptor/retinoid X receptor (LXR/RXR) heterodimers and their ligands oxysterols and retinoids. In the present study, we show that the oxysterol/retinoid-induced transcription of the ABCAl gene is modulated by the ubiquitous transcription factor Sp1 that binds to the proximal ABCA1 promoter, adjacently to the LXR/RXR responsive element. The response of the ABCA1 gene to oxysterols/retinoids as well as the ligand-inducible recruitment of Sp1 and RXR alpha/LXR alpha heterodimers to the ABCA1 promoter was blocked by mithramycin A, a well-known Sp1 inhibitor. Using SL2 cells which lack endogenous Sp1, we showed that activation of the ABCAl promoter by LXR alpha/RXR alpha heterodimers and their ligands requires Sp1. Functional interactions between these factors were demonstrated using the GAL4 transactivation system. Using both in vitro and in vivo assays, we show that physical interactions between Sp1 and LXR alpha require the N-terminal region of LXR alpha, which includes the AF1 and DNA binding domains and two different domains of Sp1: the transactivation domain B and the DNA binding domain. Overall, the present study revealed a novel mechanism of regulation of the human ABCA1 transporter which involves synergistic interactions between oxysterol/retinoid-inducible hormone nuclear receptors and the transcription factor Sp1.
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收藏
页码:11473 / 11483
页数:11
相关论文
共 60 条
[51]   Estrogen-induced retinoic acid receptor α1 gene expression:: Role of estrogen receptor Sp1 complex [J].
Sun, GL ;
Porter, W ;
Safe, S .
MOLECULAR ENDOCRINOLOGY, 1998, 12 (06) :882-890
[52]  
Suske G, 2000, Methods Mol Biol, V130, P175
[53]   Regulation of interaction of the acetyltransferase region of p300 and the DNA-binding domain of Sp1 on and through DNA binding [J].
Suzuki, T ;
Kimura, A ;
Nagai, R ;
Horikoshi, M .
GENES TO CELLS, 2000, 5 (01) :29-41
[54]   Physical interaction between retinoic acid receptor and Sp1: Mechanism for induction of urokinase by retinoic acid [J].
Suzuki, Y ;
Shimada, J ;
Shudo, K ;
Matsumura, R ;
Crippa, MP ;
Kojima, S .
BLOOD, 1999, 93 (12) :4264-4276
[55]   Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I [J].
Timmins, JM ;
Lee, JY ;
Boudyguina, E ;
Kluckman, KD ;
Brunham, LR ;
Mulya, A ;
Gebre, AK ;
Coutinho, JM ;
Colvin, PL ;
Smith, TL ;
Hayden, MR ;
Maeda, N ;
Parks, JS .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (05) :1333-1342
[56]   Transcriptional activation of transforming growth factor α by estradiol:: requirement for both a GC-rich site and an estrogen response element half-site [J].
Vyhlidal, C ;
Samudio, I ;
Kladde, MP ;
Safe, S .
JOURNAL OF MOLECULAR ENDOCRINOLOGY, 2000, 24 (03) :329-338
[57]   THE HIGH-DENSITY LIPOPROTEIN-INDUCED AND APOLIPOPROTEIN A-I-INDUCED MOBILIZATION OF CELLULAR CHOLESTEROL IS IMPAIRED IN FIBROBLASTS FROM TANGIER DISEASE SUBJECTS [J].
WALTER, M ;
GERDES, U ;
SEEDORF, U ;
ASSMANN, G .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1994, 205 (01) :850-856
[58]   Specific binding of ApoA-I, enhanced cholesterol efflux, and altered plasma membrane morphology in cells expressing ABC1 [J].
Wang, N ;
Silver, DL ;
Costet, P ;
Tall, AR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (42) :33053-33058
[59]   p300 collaborates with Sp1 and Sp3 in p21waf1/cip1 promoter activation induced by histone deacetylase inhibitor [J].
Xiao, HY ;
Hasegawa, T ;
Isobe, K .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (02) :1371-1376
[60]   Coactivator and corepressor complexes in nuclear receptor function [J].
Xu, L ;
Glass, CK ;
Rosenfeld, MG .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 1999, 9 (02) :140-147