Transcriptional regulation of ATP-binding cassette transporter A1 expression by a novel signaling pathway.
ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound protein that regulates the efflux of cholesterol derived from internalized lipoproteins. Using a mouse macrophage cell line, this report studied the impact of low-density lipoproteins (LDL) on ABCA1 expression and the signaling pathway responsible for lipoprotein-induced ABCA1 expression. Our data demonstrated that treatment of macrophages with LDL increased ABCA1 mRNA and protein levels 4.3- and 3.5-fold, respectively. LDL also induced an ∼2-fold increase in macrophage surface expression of ABCA1 and a 14-fold-increase in apolipoprotein AI-mediated cholesterol efflux. In addition, LDL significantly increased the level of phosphorylated specificity protein 1 (Sp1) and the amount of Sp1 bound to the ABCA1 promoter without alteration in total Sp1 protein level. Mutation of the Sp1 binding site in the ABCA1 promoter and inhibition of Sp1 DNA binding with mithramycin A suppressed the ABCA1 promoter activity and reduced the ABCA1 expression level induced by LDL. LDL treatment also elevated protein kinase C-ζ (PKC-ζ) phosphorylation and induced PKC-ζ binding with Sp1. Inhibition of PKC-ζ with kinase inhibitors or overexpression of kinase-dead PKC-ζ attenuated Sp1 phosphorylation and ABCA1 expression induced by LDL. These results demonstrate for the first time that activation of the PKCζ-Sp1 signaling cascade is a mechanism for regulation of LDL-induced ABCA1 expression.
Department of Physiology, Meharry Medical College, Nashville, Tennessee 37208, USA.
Xinping
X
Chen
Yanfeng
Y
Zhao
Zhongmao
Z
Guo
Lichun
L
Zhou
Emmanuel U
EU
Okoro
Hong
H
Yang
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D008926:Plicamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020218:Response Elements / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D000099221:Protein Kinase C zeta
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D008077:Lipoproteins, LDL; D008926:Plicamycin; D011493:Protein Kinase C; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D000099221:Protein Kinase C zeta; C066851:mithramycin A
J Clin Invest. 2002 Jul;110(1):35-42
12093886
Free Radic Biol Med. 2003 Aug 1;35(3):266-76
12885588
Mol Cancer Ther. 2009 Mar;8(3):543-51
19258428
Nat Med. 2002 Nov;8(11):1243-8
12411951
Nat Genet. 1999 Aug;22(4):336-45
10431236
J Thromb Haemost. 2007 Dec;5(12):2529-36
17922810
Mol Cell. 2001 Jan;7(1):161-71
11172721
J Biol Chem. 2001 Nov 23;276(47):43564-9
11559713
J Clin Invest. 1991 Nov;88(5):1613-21
1834700
Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):266-71
9874807
Biochemistry. 2007 Oct 16;46(41):11473-83
17887732
J Immunol. 2003 Oct 1;171(7):3734-41
14500673
Nat Genet. 2000 Feb;24(2):192-6
10655069
J Biol Chem. 1991 Aug 25;266(24):15771-81
1874734
Int J Obes Relat Metab Disord. 2003 Dec;27 Suppl 3:S35-40
14704742
Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):128-34
15499044
Cardiovasc Res. 2005 Dec 1;68(3):425-32
16099444
Curr Biol. 1998 Sep 24;8(19):1069-77
9768361
Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):929-34
16456089
Free Radic Biol Med. 2010 Aug 1;49(3):487-92
20478378
J Biol Chem. 2000 Sep 8;275(36):28240-5
10858438
J Lipid Res. 2007 Dec;48(12):2571-8
17720994
J Biol Chem. 1999 Nov 26;274(48):34327-36
10567409
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6298-303
11972062
Arterioscler Thromb Vasc Biol. 2003 Jul 1;23(7):1178-84
12738681
Free Radic Biol Med. 2009 Oct 15;47(8):1221-9
19666105
Biochem Pharmacol. 2000 Sep 1;60(5):635-42
10927021
Cancer Res. 2008 Sep 15;68(18):7587-96
18794147