Altered VDR-mediated transcriptional activity in prostate cancer stroma
Altered VDR-mediated transcriptional activity in prostate cancer stroma
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DOI：
10.1016/j.jsbmb.2006.12.072
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发表时间：
2007-03-01
影响因子：
4.1
通讯作者：
Onate, Sergio A.
中科院分区：
文献类型：
--
作者：
Hidalgo, Alejandro A.;Paredes, Roberto;Onate, Sergio A.
在25-羟基-维生素D-3-24-羟化酶（CYP 24）基因启动子的控制下，使用腺病毒荧光素酶表达报告基因分析了人前列腺细胞原代培养物中1 α，25-二羟基-维生素D-3（1 α，25（OH）（2）D-3）介导的基因转录。从人类临床样品的良性和恶性相关基质（BAS和CAS）分离的基质细胞已被确定含有相似水平的功能性1 α，25（OH）（2）D-3受体（VDR）。然而，已经发现，与BAS中的14-16倍相比，VDR介导的荧光素酶报告基因的报告基因活性在CAS中受限7-9倍。染色质免疫沉淀（ChIP）试验表明，在添加配体的情况下，VDR与两种细胞类型中的类维生素A和甲状腺激素（SMRT）辅阻遏物的沉默介体相互作用，CAS中的招募率高于BAS细胞。与BAS相比，在添加配体的情况下，CAS细胞中的VDR表现出配体诱导的DNA结合活性降低，辅助调节因子SRC-1和CBP的募集改变，SMRT辅助抑制因子的募集增加。此外，野生型VDR的过表达恢复了VDR介导的CYP 24荧光素酶报告基因的传递。这些结果表明，VDR结构/功能和1 α，25（OH）（2）D-3调节基因的辅助调节因子募集在CaP基质微环境中发生了改变。(c)2006年爱思唯尔有限公司保留所有战斗。
The 1 alpha,25-dihydroxy-vitamin D-3 (1 alpha,25(OH)(2)D-3) mediated gene transcription in primary cultures of human prostate cells was analyzed using an adenoviral luciferase expression reporter under the control of the 25-hydroxy-vitamin D-3-24-hydroxylase (CYP24) gene promoter. Stromal cells isolated from benign and malignant associated stroma (BAS and CAS) of a human clinical sample have been determined to contain similar levels of functional 1 alpha,25(OH)(2)D-3 receptor (VDR). However, VDR-mediated reporter activity of the luciferase reporter has been found to be limited 7-9-fold in CAS compared to 14-16-fold in BAS. Chromatin immunoprecipitation (ChIP) assays indicate that in the absence of added ligand VDR interact with the silencing mediator for retinoid and thyroid hormone (SMRT) corepressor in both cell types, with higher recruitment in CAS as compared to BAS cells. In the presence of added ligand, VDR in CAS cells exhibited decreased ligand-inducible DNA binding activity, altered recruitment of coregulators SRC-1 and CBP, and increased recruitment of SMRT corepressor, as compared to BAS. Additionally, overexpression of wild-type VDR recovered VDR-mediated transaction of CYP24 luciferase reporter. These results indicate that VDR structure/function and coregulator recruitment to 1 alpha,25(OH)(2)D-3 regulated genes is altered in the CaP stroma microenvironment. (c) 2006 Elsevier Ltd. All fights reserved.