DIFFERENTIAL GENE REGULATION IN NORMAL & TRANSFORMED KERATINOCYTES BY 1,25(OH)2

正常情况下的差异基因调控

基本信息

批准号：
8169729
负责人：
DANIEL David BIKLE
金额：
$ 0.35万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-12 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8169729
关键词：
Acids Binding Cell Line Complex Computer Retrieval of Information on Scientific Projects Database DNA Sequence Funding Gene Expression Gene Expression Regulation Genes Genetic Transcription Grant Human Institution Ligands Link Malignant Epithelial Cell Malignant Neoplasms Mediating Nuclear Extract Nuclear Hormone Receptors Prevention Proteins RNA Polymerase II RXR Recruitment Activity Research Research Personnel Resources Response Elements Source Squamous cell carcinoma Steroid Receptors Thyroid Gland Transcription Initiation Tretinoin Undifferentiated United States National Institutes of Health VDR interacting protein complex DRIP Vitamin A Vitamin D Vitamin D Response Element cofactor hormone response element human RIPK1 protein keratinocyte keratinocyte differentiation promoter receptor receptor binding response

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The active metabolites of vitamin D and vitamin A show promise in the prevention and treatment of a number of malignancies including squamous cell carcinoma (SCC). 1,25(OH)2D regulates gene expression through its nuclear hormone receptor VDR. VDR partners with the retinoic X (RXR) and retinoic acid (RAR) receptors which bind the active metabolites of vitamin A, 9cis retinoic acid (9cisRA) and all trans retinoic acid (tRA), respectively. VDR, RXR, and RAR form heterodimers, which stimulate gene expression through specific sequences of DNA in the promoter of genes called hormone response elements. Different vitamin D responsive genes have different response elements and are differentially regulated by 1,25(OH)2D and RA in normal human keratinocytes (NHK). Squamous carcinoma cell lines (SCC) fail to respond to 1,25(OH)2D or RA in the same manner as NHK. The SCC lines we have studied have normal levels of VDR with normal binding of the VDR to its ligand and normal binding of the VDR to the vitamin D response elements (VDRE). Therefore, the explanation for the loss of response of SCC to 1,25(OH)2D has been unclear. However, it has recently been discovered that nuclear hormone receptors such as VDR, RAR, and RXR interact with a number of coactivators and cosuppressors which link the nuclear hormone receptors bound to their respective response elements to the transcription initiation complex where transcription by RNA polymerase II begins. During the previous funding period we discovered that the principal binding complex to VDR in nuclear extracts from undifferentiated normal keratinocytes is DRIP (vitamin D receptor interacting protein), a complex essentially identical to TRAP (thyroid receptor activating protein) and ARC (activator-recruited cofactor) which were identified by their binding to other nuclear hormone receptors. During normal keratinocyte differentiation DRIP is downregulated. Its binding to VDR is replaced by two SRC (steroid receptor coactivator). More recently we found that hairless acts as a suppressor of VDR action. We are currently involved in determining the factors that mediate this suppressor action of hairless on VDR.

该副本是利用众多研究子项目之一由NIH/NCRR资助的中心赠款提供的资源。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是对于中心，这不一定是调查员的机构。维生素D和维生素A的活性代谢物在预防和治疗包括鳞状细胞癌（SCC）在内的许多恶性肿瘤方面表现出了希望。 1,25（OH）2D通过其核激素受体VDR调节基因表达。 VDR与视黄X（RXR）和视黄酸（RAR）受体合作，它们分别结合了维生素A，9cis视黄酸（9cisra）和所有反式视黄酸（TRA）的活性代谢产物。 VDR，RXR和RAR形成异二聚体，它们通过在称为激素反应元件的基因启动子中通过DNA的特定序列刺激基因表达。不同的维生素D反应基因具有不同的反应元件，并且在正常人角质形成细胞（NHK）中受1,25（OH）2d和RA的差异调节。鳞状癌细胞系（SCC）无法以与NHK相同的方式对1,25（OH）2D响应。我们研究的SCC线具有正常水平的VDR水平，其VDR与其配体的正常结合以及VDR与维生素D反应元件（VDRE）的正常结合。因此，尚不清楚SCC对1,25（OH）2D反应丧失的解释。然而，最近已经发现，诸如VDR，RAR和RXR之类的核激素受体与许多共激活剂和cesuplastor相互作用，这些共激活剂和cesu抑制剂将核激素受体与其各自的响应元件结合到转录起始复合物与RNA聚合酶II转录的转录起始复合物之间。在上一个资金期间，我们发现，来自未分化的正常角质形成细胞中的核提取物与VDR的主要结合复合物是滴水（维生素D受体相互作用蛋白），这是一种基本上与捕集诱捕物（甲状腺受体激活蛋白）和ARC（激活剂cofcofactors cofactor）的复合物相同，通过其与其他核能相结合。在正常的角质形成细胞分化期间，滴水被下调。它与VDR的结合被两个SRC（类固醇受体共激活因子）所取代。最近，我们发现无毛是VDR动作的抑制器。目前，我们参与了介导无毛在VDR的抑制作用作用的因素。