Regulation of Cyclin D1 Expression and DNA Synthesis by Phosphatidylinositol 3-Kinase in Airway Smooth Muscle Cells

We have shown in bovine tracheal myocytes that extracellular signal-regulated kinase (ERK) and Rac1 function as upstream activators of transcription from the cyclin D1 promoter. We now examine the role of phosphatidylinositol (PI) 3-kinase in this process. PI 3-kinase activity was increased by platelet-derived growth factor (PDGF) and attenuated by the PI 3-kinase inhibitors wortmannin and LY294002. These inhibitors also decreased cyclin D1 promoter activity, protein abundance, and DNA synthesis. Overexpression of the active catalytic subunit of PI 3-kinase (p110PI 3-KCAAX) was sufficient to activate the cyclin D1 promoter. Wortmannin and LY294002 failed to attenuate PDGF-induced ERK activation, and overexpression of p110PI 3-KCAAX was insufficient to activate ERK. p110PI 3-KCAAX-induced cyclin D1 promoter activity was not blocked by PD98059, an inhibitor of mitogen-activated protein kinase/ERK kinase. We next examined whether PI 3-kinase and the 21-kD guanidine triphosphatase Rac1 regulate cyclin D1 prom...