Department of Nutrition Science, Purdue University, West Lafayette, IN 47907-2059, United States.
Mol Cell Endocrinol. 2012 Sep 25;361(1-2):31-9. doi: 10.1016/j.mce.2012.03.008. Epub 2012 Mar 28.
Phorbol 12-myristate 13-acetate (PMA) increased 1,25(OH)(2)D(3)-induced human 25 hydroxyvitamin d-24 hydroxylase (hCYP24A1) gene expression and vitamin D receptor (VDR) binding to the hCYP24A1 promoter. It did not alter transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression, VDR binding to the TRPV6 promoter, or VDR binding to a crude chromatin preparation. PMA activated Extracellular signal-Regulated Kinases (ERK) 1/2 and p38 mitogen activated protein kinases (MAPK) and inhibiting these kinases reduced 1,25(OH)(2)D(3)-induced and PMA-enhanced hCYP24A1 promoter activity. Mithramycin A inhibits Specific Protein (Sp) family member binding to DNA and reduced 1,25(OH)(2)D(3)-induced and PMA-enhanced hCYP24A1 promoter activity. Sp1 or Sp3 siRNA knockdown reduced 1,25(OH)(2)D(3)-regulated hCYP24A1 promoter activity but only Sp3 siRNA reduced PMA-enhanced hCYP24A1 promoter activity. PMA increased MAPK-dependent Sp3 phosphorylation, Sp3-VDR interactions, and Sp3 binding to the hCYP24A1 promoter. These data suggest that MAPK signaling contributes to 1,25(OH)(2)D(3)-induced and PMA-enhanced CYP24A1 gene transcription by modulating Sp3 function.
佛波醇 12-肉豆蔻酸 13-醋酸酯 (PMA) 增加了 1,25(OH)(2)D(3)诱导的人 25 羟维生素 D-24 羟化酶 (hCYP24A1) 基因表达和维生素 D 受体 (VDR) 与 hCYP24A1 启动子的结合。它不会改变瞬时受体电位阳离子通道，亚家族 V，成员 6 (TRPV6) 的表达，VDR 与 TRPV6 启动子的结合，或 VDR 与粗染色质制剂的结合。PMA 激活细胞外信号调节激酶 (ERK) 1/2 和 p38 有丝分裂原激活蛋白激酶 (MAPK)，抑制这些激酶减少了 1,25(OH)(2)D(3)诱导和 PMA 增强的 hCYP24A1 启动子活性。米托蒽醌 A 抑制特定蛋白 (Sp) 家族成员与 DNA 的结合，并减少了 1,25(OH)(2)D(3)诱导和 PMA 增强的 hCYP24A1 启动子活性。Sp1 或 Sp3 siRNA 敲低减少了 1,25(OH)(2)D(3)调节的 hCYP24A1 启动子活性，但只有 Sp3 siRNA 减少了 PMA 增强的 hCYP24A1 启动子活性。PMA 增加了 MAPK 依赖性 Sp3 磷酸化、Sp3-VDR 相互作用以及 Sp3 与 hCYP24A1 启动子的结合。这些数据表明，MAPK 信号通过调节 Sp3 功能，有助于 1,25(OH)(2)D(3)诱导和 PMA 增强的 CYP24A1 基因转录。
