p21 expression is induced by activation of nuclear nerve growth factor-induced Balpha (Nur77) in pancreatic cancer cells.
p21 expression is induced by activation of nuclear nerve growth factor-induced Balpha (Nur77) in pancreatic cancer cells.
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DOI：
10.1158/1541-7786.mcr-08-0473
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Safe S
中科院分区：
文献类型：
--
作者：
Lee SO;Chintharlapalli S;Liu S;Papineni S;Cho SD;Yoon K;Safe S
1,1-二（3′-吲哚基）-1-（对茴香基）甲烷（DIM-C-pPhOCH3）在癌细胞中激活孤儿受体神经生长因子诱导的Bα (NGFI-Bα或Nur77)，在本研究中，DIM-C-pPhOCH3降低胰腺癌细胞Panc1存活并在G0/G1期阻滞细胞。这些反应伴随着胰腺癌细胞周期蛋白依赖性激酶抑制剂p21的诱导。机制研究表明，DIMC-pPhOCH3对p21 mRNA和蛋白的诱导依赖于nur77，而不依赖于同样由DIMC-pPhOCH3诱导的kr<s:1> ppel样因子-4。dim - c - phoch3构建的p21启动子的激活需要启动子的近端富含gc， RNA干扰研究结果表明，p21启动子依赖nur77的激活涉及Sp1和Sp4的相互作用，但不涉及Sp3。在用DIM-C-pPhOCH3处理的Panc1细胞中，Nur77与p21启动子的相互作用也在染色质免疫沉淀试验中得到证实。这些数据表明，核Nur77的激活导致了p21诱导的新途径，该途径不依赖于Nur77应答元件，但依赖于与p21启动子近端富含gc的区域结合的Sp蛋白。
1,1-Bis(3'-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH3) activates the orphan receptor nerve growth factor-induced Bα (NGFI-Bα or Nur77) in cancer cells and, in this study, DIM-C-pPhOCH3 decreased Panc1 pancreatic cancer cell survival and arrested cells in G0/G1. These responses were accompanied by induction of the cyclin-dependent kinase inhibitor p21 in pancreatic cancer cells. Mechanistic studies demonstrated that induction of p21 mRNA and protein by DIM-C-pPhOCH3 was Nur77-dependent but did not depend on Krüppel-like factor-4 which was also induced by DIMC-pPhOCH3. Activation of p21 promoter constructs by DIM-C-pPhOCH3 required the GC-rich proximal region of the promoter, and results of RNA interference studies showed that Nur77-dependent activation of the p21 promoter involved interactions with Sp1 and Sp4 but not Sp3. Interactions of Nur77 with the p21 promoter in Panc1 cells treated with DIM-C-pPhOCH3 were also confirmed in chromatin immunoprecipitation assays. These data show that activation of nuclear Nur77 results in a novel pathway for induction of p21 which is independent of Nur77 response elements but dependent on Sp proteins bound to the GC-rich proximal region of the p21 promoter.