Bai Yun, Pontoglio Marco, Hiesberger Thomas, Sinclair Angus M, Igarashi Peter
Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 75390, USA.
Am J Physiol Renal Physiol. 2002 Oct;283(4):F839-51. doi: 10.1152/ajprenal.00128.2002.
Kidney-specific cadherin (Ksp-cadherin) is a tissue-specific member of the cadherin family that is expressed exclusively in the kidney and developing genitourinary tract. Recent studies have shown that the proximal 250 bp of the Ksp-cadherin gene promoter are sufficient to direct tissue-specific gene expression in vivo and in vitro. The proximal 120 bp of the promoter are evolutionarily conserved between mouse and human and contain a DNase I hypersensitive site that is kidney cell specific. At position -55, the promoter contains a consensus recognition site for hepatocyte nuclear factor-1 (HNF-1). Mutations of the consensus HNF-1 site and downstream GC-boxes inhibit promoter activity in transfected cells. HNF-1alpha and HNF-1beta bind specifically to the -55 site, and both proteins transactivate the promoter directly. Expression of Ksp-cadherin is not altered in the kidneys of HNF-1alpha-deficient mice. However, expression of a gain-of-function HNF-1beta mutant stimulates Ksp-cadherin promoter activity in transfected cells, whereas expression of a dominant-negative mutant inhibits activity. These studies identify Ksp-cadherin as the first kidney-specific promoter that has been shown to be regulated by HNF-1beta. Mutations of HNF-1beta, as occur in humans with inherited renal cysts and diabetes, may cause dysregulated Ksp-cadherin promoter activity.
肾特异性钙黏蛋白（Ksp-钙黏蛋白）是钙黏蛋白家族的一种组织特异性成员，仅在肾脏和发育中的泌尿生殖道中表达。最近的研究表明，Ksp-钙黏蛋白基因启动子近端的250 bp足以在体内和体外指导组织特异性基因表达。启动子近端的120 bp在小鼠和人类之间具有进化保守性，并包含一个肾细胞特异性的DNase I超敏位点。在-55位置，启动子包含肝细胞核因子-1（HNF-1）的共有识别位点。共有HNF-1位点和下游GC盒的突变会抑制转染细胞中的启动子活性。HNF-1α和HNF-1β特异性结合-55位点，并且这两种蛋白都直接反式激活启动子。在HNF-1α缺陷小鼠的肾脏中，Ksp-钙黏蛋白的表达没有改变。然而，功能获得性HNF-1β突变体的表达会刺激转染细胞中的Ksp-钙黏蛋白启动子活性，而显性负性突变体的表达则会抑制活性。这些研究确定Ksp-钙黏蛋白是第一个被证明受HNF-1β调控的肾脏特异性启动子。HNF-1β的突变，如在患有遗传性肾囊肿和糖尿病的人类中发生的突变，可能会导致Ksp-钙黏蛋白启动子活性失调。
