Vitamin D3 inducible Genes Mediating Differentiation

维生素 D3 诱导基因介导分化

• 批准号: 6334418
• 负责人: LEONARD P FREEDMAN
• 金额: $ 28.65万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-27 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6334418
• 关键词: cell differentiation; cholecalciferol; gene induction /repression; genetic promoter element; homeobox genes; hormone regulation /control mechanism; microarray technology; myelogenous leukemia; neoplasm /cancer genetics; nutrition aspect of cancer; nutrition related tag; oncoprotein p21; receptor expression; transcription factor; vitamin D receptors

DESCRIPTION: (Scanned from the applicant's abstract) The goal of this competing renewal is to further our elucidation of the molecular events leading to myeloid leukemic cell differentiation in response to the hormone 1,25 dihydroxyvitamin D3 [1 ,25(OH)2D3}. We will focus on two vitamin D receptor (VDR? target genes central to the induction of growth arrest and differentiation in the myeloid cell system: p21waf1,cip, and HoxAlO. In addition, myeloid differentiation will be used as cellular readout for the 1 ,25(OH)2D3 response in the context of nuclear receptor coactivator function, as well as when VDR function is attenuated by chromosomal translocations involving the RARa gene. The specific aims during the proposed grant period are to: 1. Characterize the complex regulation of the p21 promoter by VDR and HoxAlO, A cluster of multiple VDr and HoxAlO binding sites in the p21 promoter individually and collectively contribute to 1,25(OH)2D3 regulation of this promoter. Nucleosomal structure and in viva occupancy of these regions will be examined in response to 1,25(OH)2D3 and HoxAlO. 2.Define the role of HoxAlO in growth arrest and cell differentiation. HoxAlO regulation of the p21 promoter, and its possible role as a transcriptional modulator of other cell cycle regulator genes, will be addressed. A screen for novel HoxAlO target genes using array technology will also be generated. 3. Describe the molecular basis for PLZF and PLZF-RARcx attenuation of 1,25 (OH)2D3-inducible myeloid differentiation. The mechanisms by which 1 ,25(OH)2D3-dependent differentiation is attenuated by PLZF and PLZFRARa will be characterized at the molecular level. 4. Utilize cell differentiation as a biological read-out for coactivator function. The functional requirement of the DRIP coactivator complex in mediating VDR and RAR transactivation, in the context of nuclear receptor-dependent myeloid differentiation, will be determined.

描述：（从申请人的摘要中扫描）该竞争的目标 更新是为了进一步阐明我们的分子事件 激素1,25的髓样白血病细胞分化 二羟基维生素D3 [1，25（OH）2d3}。我们将专注于两个维生素D受体 （VDR？靶基因诱导生长停滞和 髓样细胞系统的分化：p21WAF1，CIP和Hoxalo。在 此外，髓样分化将用作1的细胞读数 ，25（OH）2d3在核受体共激活函数的背景下响应， 以及何时通过涉及的染色体易位来减弱VDR功能 拉拉基因。在拟议的赠款期间的具体目标是：1。 表征了VDR和Hoxalo对P21启动子的复杂调节，A P21启动子中多个VDR和Hoxalo结合位点的簇 单独和集体贡献了1,25（OH）2d3的规定 发起人。这些区域的核小体结构和体内占用率将是 对1,25（OH）2d3和Hoxalo进行了检查。 2.定义Hoxalo在 生长停滞和细胞分化。 p21启动子的Hoxalo调节 并可能作为其他细胞周期的转录调节剂的作用 调节基因将被解决。新型Hoxalo靶基因的屏幕 使用阵列技术也将生成。 3。描述分子基础 对于1,25（OH）2d3诱导的髓样的PLZF和PLZF-RARCX衰减 分化。 1，25（OH）2d3依赖性分化的机制 由PLZF衰减，PLZFRARA将在分子上进行表征 等级。 4。利用细胞分化作为共激活因子的生物学读出 功能。滴水共激活器复合物的功能需求 在核的背景下介导VDR和RAR反式激活 将确定受体依赖性髓样分化。