Peroxisome proliferator-activated receptor γ is a Zac target gene mediating Zac antiproliferation
Peroxisome proliferator-activated receptor γ is a Zac target gene mediating Zac antiproliferation
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DOI：
10.1158/0008-5472.can-06-1529
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发表时间：
2006-12-15
期刊：
影响因子：
11.2
通讯作者：
Spengler, Dietmar
中科院分区：
文献类型：
--
作者：
Barz, Thomas;Hoffmann, Anke;Spengler, Dietmar
Zac是一种C2H2锌指蛋白，通过DNA结合和反式激活调节细胞凋亡和细胞周期阻滞。在肿瘤发生和有丝分裂激活的反应中，Zac基因表达以甲基化敏感的方式下调。到目前为止，还没有发现可以解释Zac有效的抗增殖功能的靶基因。在这里，应用全基因组表达分析，我们确定过氧化物酶体增殖物激活受体γ（PPAR γ）作为一个新的真正的Zac靶基因，这是由直接Zac结合到近端的PPAR γ 1启动子诱导。我们发现，在人类结肠癌细胞中，ZAC激活的PPAR γ靶基因的表达，在一个依赖于PPAR γ的方式。此外，我们发现，治疗垂体瘤细胞与奥曲肽，生长抑素类似物，导致ZAC诱导和随后的ZAC依赖性上调的过氧化物酶体增殖物激活受体γ，从而介导的ZAC的抗增殖活性的一部分。我们的工作为阐明Zac和PPAR γ之间的功能关系迈出了第一步，这可能与肿瘤发生和糖尿病的理解有关。
Zac is a C2H2 zinc finger protein, which regulates apoptosis and cell cycle arrest through DNA binding and transactivation. During tumorigenesis and in response to mitogenic activation, Zac gene expression is down-regulated in a methylation-sensitive manner. As yet, no target genes have been identified that could explain the potent antiproliferative function of Zac. Here, applying genome-wide expression analysis, we identify peroxisome proliferator-activated receptor gamma (PPAR gamma) as a new bona fide Zac target gene, which is induced by direct Zac binding to the proximal PPAR gamma 1 promoter. We show that in human colon carcinoma cells, ZAC activates expression of PPAR gamma target genes in a PPAR gamma-dependent manner. Moreover, we show that treatment of pituitary tumor cells with octreotide, a somatostatin analogue, leads to Zac induction and subsequent Zac-dependent up-regulation of PPAR gamma, which thereupon mediates part of the antiproliferative activity of Zac. Our work provides a first step toward elucidating a functional relationship between Zac and PPAR gamma that could be relevant to the understanding of tumorigenesis and diabetes as well.