Page K, Li J, Hershenson M B
Department of Pediatrics, University of Chicago, Chicago, Illinois 60637-1470, USA.
Am J Physiol Lung Cell Mol Physiol. 2001 May;280(5):L955-64. doi: 10.1152/ajplung.2001.280.5.L955.
We have demonstrated that platelet-derived growth factor (PDGF) stimulates p38 mitogen-activated protein (MAP) kinase activation in bovine tracheal myocytes, suggesting that p38 is involved in growth regulation. We therefore examined whether p38 regulates expression of cyclin D1, a G(1) cyclin required for cell cycle traversal. The chemical p38 inhibitors SB-202190 and SB-203580 each increased basal and PDGF-induced cyclin D1 promoter activity and protein abundance. Overexpression of a dominant negative allele of MAP kinase kinase-3 (MKK3), an upstream activator of p38alpha, had similar effects. Conversely, active MKK3 and MKK6, both of which increase p38alpha activity, each decreased transcription from the cyclin D1 promoter. Together, these data demonstrate that p38 negatively regulates cyclin D1 expression. We tested whether p38 regulates cyclin D1 expression via inhibition of extracellular signal-regulated kinase (ERK) activation. Chemical inhibitors of p38 induced modest ERK phosphorylation and activation. However, dominant negative MKK3 was insufficient to activate ERK, and active MKK3 and MKK6 did not attenuate platelet-derived growth factor-mediated ERK activation. These data are consistent with the notion that p38alpha negatively regulates cyclin D1 expression via an ERK-independent pathway.
我们已经证明，血小板衍生生长因子（PDGF）可刺激牛气管肌细胞中p38丝裂原活化蛋白（MAP）激酶的激活，这表明p38参与生长调节。因此，我们研究了p38是否调节细胞周期蛋白D1的表达，细胞周期蛋白D1是细胞周期进程所需的一种G1期细胞周期蛋白。化学p38抑制剂SB-202190和SB-203580均可增加基础和PDGF诱导的细胞周期蛋白D1启动子活性及蛋白丰度。p38α的上游激活剂丝裂原活化蛋白激酶激酶-3（MKK3）的显性负等位基因的过表达也有类似作用。相反，可增加p38α活性的活性MKK3和MKK6均降低了细胞周期蛋白D1启动子的转录。这些数据共同表明，p38负向调节细胞周期蛋白D1的表达。我们测试了p38是否通过抑制细胞外信号调节激酶（ERK）激活来调节细胞周期蛋白D1的表达。p38的化学抑制剂可诱导适度的ERK磷酸化和激活。然而，显性负性MKK3不足以激活ERK，而活性MKK3和MKK6并未减弱血小板衍生生长因子介导的ERK激活。这些数据与p38α通过ERK非依赖途径负向调节细胞周期蛋白D1表达的观点一致。
