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

正常情况下的差异基因调控

• 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
• 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

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 维生素D和维生素A的活性代谢产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显示出希望。 1，25（OH）2D通过其核激素受体VDR调节基因表达。 VDR与维A酸X（RXR）和维A酸（RAR）受体结合，后者分别结合维生素A的活性代谢物9顺式维A酸（9 cisRA）和全反式维A酸（tRA）。 VDR、RXR和RAR形成异源二聚体，通过称为激素反应元件的基因启动子中的特定DNA序列刺激基因表达。 不同的维生素D应答基因具有不同的应答元件，并且在正常人角质形成细胞（NHK）中受到1，25（OH）2D和RA的差异调节。鳞状细胞癌细胞系（SCC）对1，25（OH）2D或RA的反应与NHK相同。 我们研究的SCC细胞系具有正常水平的VDR，VDR与其配体的结合正常，VDR与维生素D反应元件（VDRE）的结合正常。因此，SCC对1，25（OH）2D反应丧失的解释尚不清楚。 然而，最近发现，核激素受体如VDR、RAR和RXR与许多共激活子和共抑制子相互作用，所述共激活子和共抑制子将与其各自的反应元件结合的核激素受体连接到转录起始复合物，其中RNA聚合酶II的转录开始。 在之前的资助期间，我们发现未分化的正常角质形成细胞的核提取物中与VDR的主要结合复合物是DRIP（维生素D受体相互作用蛋白），这是一种与TRAP（甲状腺受体活化蛋白）和ARC（活化剂募集辅因子）基本相同的复合物，通过它们与其他核激素受体的结合来鉴定。 在正常角质形成细胞分化过程中，DRIP下调。 它与VDR的结合被两个SRC（类固醇受体共激活因子）取代。 最近，我们发现，无毛作为VDR作用的抑制剂。 我们目前正在参与确定介导无毛对VDR的抑制作用的因素。