Zhang Qin, Adiseshaiah Pavan, Kalvakolanu Dhananjaya V, Reddy Sekhar P
Department of Environmental Health Sciences, Bloomberg School of Public Health and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
J Biol Chem. 2006 Apr 14;281(15):10174-81. doi: 10.1074/jbc.M513008200. Epub 2006 Feb 20.
The FRA-1 proto-oncogene is overexpressed in a variety of human tumors and is known to up-regulate the expression of genes involved in tumor progression and invasion. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway is also known to regulate these cellular processes. More importantly, respiratory toxicants and carcinogens activate both the PI3K-Akt pathway and FRA-1 expression in human bronchial epithelial (HBE) cells. In this study we investigated a potential link between the PI3K-Akt pathway and the cigarette smoke (CS)-stimulated epidermal growth factor receptor-mediated FRA-1 induction in non-oncogenic HBE cells. Treatment of cells with LY294002, an inhibitor of the PI3K-Akt pathway, completely blocked CS-induced FRA-1 expression. Surprisingly pharmacological inhibition of Akt had no significant effect on CS-induced FRA-1 expression. Likewise the inhibition of protein kinase C zeta, which is a known downstream effector of PI3K, did not alter FRA-1 expression. We found that the PI3K through p21-activated kinase 1 regulates FRA-1 proto-oncogene induction by CS and the subsequent activation of the Elk1 and cAMP-response element-binding protein transcription factors that are bound to the promoter in HBE cells.
FRA-1原癌基因在多种人类肿瘤中过度表达，并且已知其会上调参与肿瘤进展和侵袭的基因的表达。磷脂酰肌醇3激酶（PI3K）-Akt信号通路也已知可调节这些细胞过程。更重要的是，呼吸道毒物和致癌物会激活人类支气管上皮（HBE）细胞中的PI3K-Akt信号通路和FRA-1表达。在本研究中，我们调查了PI3K-Akt信号通路与香烟烟雾（CS）刺激的表皮生长因子受体介导的非致癌性HBE细胞中FRA-1诱导之间的潜在联系。用PI3K-Akt信号通路抑制剂LY294002处理细胞，完全阻断了CS诱导的FRA-1表达。令人惊讶的是，对Akt的药理学抑制对CS诱导的FRA-1表达没有显著影响。同样，对蛋白激酶Cζ（PI3K的已知下游效应器）的抑制也未改变FRA-1表达。我们发现，PI3K通过p21活化激酶1调节CS诱导的FRA-1原癌基因诱导以及随后在HBE细胞中与启动子结合的Elk1和cAMP反应元件结合蛋白转录因子的激活。
