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A novel signaling pathway for regulation of ATP‐binding cassette transporter A1 expression
Author(s) -
Yang Hong,
Chen Xinping,
Zhang Hongfeng,
Lin Xinghua,
Okoro Emmanuel U,
Zhou LiChun,
Guo Zhongmao
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.714.4
Subject(s) - abca1 , gene knockdown , protein kinase c , microbiology and biotechnology , kinase , chemistry , signal transduction , biology , biochemistry , transporter , gene
The objective of this study is to characterize the signaling pathway for regulation of ATP‐binding cassette transporter A1 (ABCA1) expression. Quantitative real‐time RT‐PCR assay and Western blot analysis revealed that treatment of macrophages with reelin, apolipoprotein E (ApoE) or ApoE‐containing lipoproteins increased ABCA1 mRNA and protein expression. In addition, these reagents significantly increased the level of phosphorylated disabled‐1 (Dab1), phosphatidylinositol 3‐kinase (PI3K), protein kinase C‐æ (PKC‐æ), and specificity protein 1 (Sp1), increased the amount of Sp1 bound to the ABCA1 promoter, and induced PKC‐æ binding with Sp1. Mutation of the Sp1 binding site in the ABCA1 promoter suppressed the ABCA1 promoter activity induced by reelin, ApoE or ApoE‐containing lipoproteins. The upregulation effect of these reagents on ABCA1 expression was suppressed by: 1) knockdown of Dab1, very low‐density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) with siRNAs, 2) inhibition of PI3K and PKC with kinase inhibitors, 3) overexpression of kinase‐dead PKC‐æ, and 4) inhibition of Sp1 DNA‐binding with mithramycin A. These results, together with the known function of these signaling proteins, suggest that ABCA1 expression can be upregulated by activation of the VLDLR/ApoER2‐Dab1‐PI3K‐PKCæ‐Sp1 signaling cascade. Grant support: SC1HL101431 (HY) and R01HL089382 (ZMG).