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Regulation of Airway Smooth Muscle Cyclin D₁ Transcription by Protein Kinase C-

Department of Pediatrics and the Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois; Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York; and Department of Medicine and Developmental and Molecular Biology, Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York

Address correspondence to: Marc B. Hershenson, M.D., University of Chicago Children's Hospital, 5841 S. Maryland Avenue, MC 4064, Chicago, IL 60637-1470. E-mail: mhershen{at}midway.uchicago.edu

The precise mechanism by which protein kinase C- (PKC) inhibits cell cycle progression is not known. We investigated the regulation of cyclin D₁ transcription by PKC in primary bovine airway smooth muscle cells. Overexpression of the active catalytic subunit of PKC attenuated platelet-derived growth factor (PDGF)-mediated transcription from the cyclin D₁ promoter, whereas overexpression of a dominant-negative PKC increased promoter activity. A PKC-specific pseudosubstrate increased cyclin D₁ protein abundance. To determine the transcriptional mechanism by which PKC negatively regulates cyclin D₁ expression, we transiently transfected cells with cDNAs encoding cyclin D₁ promoter 5' deletions and site mutations in the context of a -66 promoter fragment. We found that the -57 to -52 CRE/ATF2 site functions as a basal level and PDGF enhancer, whereas the -39 to -30 nuclear factor-B site functions as a basal level suppressor. Further, PDGF and PKC responsiveness of the cyclin D₁ promoter was maintained following 5' deletion to the Ets-containing -22 minimal promoter. Finally, using electrophoretic mobility gel shift and reporter assays, we determined that PKC inhibits CRE/ATF2 binding and transactivation, activates nuclear factor-B binding and transactivation, and attenuates Ets transactivation. These data suggest that PKC attenuates cyclin D₁ promoter activity via the regulation of three distinct cis-acting regulatory elements.

Abbreviations: activating transcription factor-2, ATF-2 • cAMP response element, CRE • CRE binding protein, CREB • cAMP-responsive element modulator, CREM • Dulbecco's Minimum Essential Medium, DMEM • extracellular signal regulated kinase, ERK • hemagglutinin, HA • mitogen-activated protein kinase, MAP kinase • myelin basic protein, MBP • nuclear factor-B, NF-B • phosphate buffered saline, PBS • platelet-derived growth factor, PDGF • phosphatidylinositol 3-kinase, PI 3 • PKC, protein kinase C • phenylmethylsulfonyl fluoride, PMSF

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