The zinc finger protein 202 (ZNF202) is a transcriptional repressor of ATP binding cassette transporter A1 (ABCA1) and ABCG1 gene expression and a modulator of cellular lipid efflux
The zinc finger protein 202 (ZNF202) is a transcriptional repressor of ATP binding cassette transporter A1 (ABCA1) and ABCG1 gene expression and a modulator of cellular lipid efflux
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DOI：
10.1074/jbc.m100218200
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发表时间：
2001-04-13
影响因子：
4.8
通讯作者：
Schmitz, G
中科院分区：
文献类型：
--
作者：
Porsch-Özcürümez, M;Langmann, T;Schmitz, G
锌指基因202（ZNF 202）位于染色体11 q23上的低血脂蛋白血症易感基因座内，是参与脂质代谢的多种基因的转录抑制因子。为了进一步证明ZNF 202与低脂蛋白血症之间的功能联系，我们研究了ZNF 202表达对ATP结合盒转运体A1（ABCA 1）和ABCG 1的影响，ABCA 1是血浆高密度脂蛋白池大小的关键调节剂，而ABCG 1是人巨噬细胞胆固醇和磷脂流出的另一种介质。我们在这里证明，全长ZNF 202 m1亚型结合ABCA 1启动子内的GnT重复序列（-229/ -210）和ABCG 1（-572/-552），ZNF 202 m1在HepG 2细胞中的表达剂量依赖性地抑制ABCA 1和ABCG 1的启动子活性，这种转录作用需要ZNF 202中SCAN结构域的存在和ABCA 1-24位TATA盒的功能完整性，而GnT结合基序的存在是不必要的。ZNF 202 SCAN结构域的寡聚化状态影响相邻ZNF 202 Kruppel相关盒结构域募集转录辅抑制因子KAP 1的能力。ZNF 202 m1在RAW264.7巨噬细胞中的过表达阻止了20（S）OH-胆固醇和9-顺式-视黄酸对ABCA 1基因表达的诱导，进一步证实了ZNF 202对转录激活的关键元件的干扰。最后，HDL和apoAI介导的脂质流出在稳定表达ZNF 202 m1的RAW 264.7细胞中显著减少，总之，我们已经确定了ABCA 1和ABCG 1作为ZNF 202介导的抑制作用的靶基因，从而为ZNF 202和低脂蛋白血症之间的功能联系提供了证据。
The zinc finger gene 202 (ZNF202) located within a hypoalphalipoproteinemia susceptibility locus on chromosome 11q23 is a transcriptional repressor of various genes involved in lipid metabolism. To provide further evidence for a functional linkage between ZNF202 and hypoalphalipoproteinemia, we investigated the effect of ZNF202 expression on ATP binding cassette transporter A1 (ABCA1) and ABCG1, ABCA1 is a key regulator of the plasma high density lipoprotein pool size, whereas ABCG1 is another mediator of cellular cholesterol and phospholipid efflux in human macrophage. We demonstrate here that the full-length ZNF202m1 isoform binds to GnT repeats within the promoters of ABCA1 (-229/ -210) and ABCG1 (-572/-552), ZNF202m1 expression in HepG2 cells dose-dependently repressed the promotor activities of ABCA1 and ABCG1, This transcriptional effect required the presence of the SCAN domain in ZNF202 and the functional integrity of a TATA box at position -24 of ABCA1, whereas the presence of GnT binding motifs was nonessential. The state of ZNF202 SCAN domain oligomerization affected the ability of the adjacent ZNF202 Kruppel-associated box domain to recruit the transcriptional corepressor KAP1, Overexpression of ZNF202m1 in RAW264.7 macrophages prevented the induction of ABCA1 gene expression by 20(S)OH-cholesterol and 9-cis-retinoic acid, further substantiating the interference of ZNF202 in critical elements of transcriptional activation, Finally, HDL and apoAI-mediated lipid efflux was significantly reduced in RAW264.7 cells stably expressing ZNF202m1, In conclusion, we have identified ABCA1 and ABCG1 as target genes for ZNF202-mediated repression and thus, provide evidence for a functional linkage between ZNF202 and hypoalphalipoproteinemia.