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Am. J. Respir. Cell Mol. Biol., Volume 23, Number 4, October, 2000 436-443

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

Kristen Page, Jing Li, Yan Wang, Sreedharan Kartha, Richard G. Pestell, and Marc B. Hershenson

Department of Pediatrics, University of Chicago, Chicago, Illinois; and Albert Einstein Cancer Center, Department of Medicine and Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York

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 promoter activity by similar mechanisms. p110PI 3-KCAAX-induced cyclin D1 promoter activity was decreased by two inhibitors of Rac1-mediated signaling, catalase and diphenylene iodonium. Further, PDGF, PI 3-kinase, and Rac1 each activated the cyclin D1 promoter at the cyclic adenosine monophosphate response element binding protein (CREB)/activating transcription factor (ATF)-2 binding site, as evidenced by expression of a CREB/ATF-2 reporter plasmid. Finally, PI 3-kinase and Rac1-induced CREB/ATF-2 transactivation were each inhibited by catalase. Together, these data suggest that in airway smooth muscle (ASM) cells, PI 3-kinase regulates transcription from the cyclin D1 promoter and DNA synthesis in an ERK-independent manner. Further, PI 3-kinase and Rac1 regulate ASM cell cycle traversal via a common cis-regulatory element in the cyclin D1 promoter.




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