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This Article Full Text Full Text (PDF) All Versions of this Article: 292/6/L1543    most recent 00430.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (20) Citing Articles via Google Scholar Google Scholar Articles by Sturrock, A. Articles by Kennedy, T. P. Search for Related Content PubMed PubMed Citation Articles by Sturrock, A. Articles by Kennedy, T. P.

Nox4 mediates TGF-1-induced retinoblastoma protein phosphorylation, proliferation, and hypertrophy in human airway smooth muscle cells

¹Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, University of Utah Health Sciences Center and Veterans Administration Medical Center, Salt Lake City, Utah; ²Division of Pediatric Pulmonary Diseases, Duke University Medical Center, Durham, North Carolina; and ³Department of Biology, Winthrop University, Rock Hill, South Carolina

Submitted 31 October 2006 ; accepted in final form 27 February 2007

Transforming growth factor-1 (TGF-1) plays a pivotal role in increasing airway smooth muscle mass in severe asthma by inducing proliferation and hypertrophy of human airway smooth muscle. The mechanism(s) for these effects of TGF-1 have not been fully elucidated. In this study, we demonstrate that TGF-1 is a potent inducer of expression of the nonphagocyte NAD(P)H oxidase catalytic homolog Nox4, diphenylene iodonium-inhibitable reactive oxygen species production, proliferation, and hypertrophy in cultured human airway smooth muscle cells. By confocal microscopy, TGF-1-induced Nox4 was localized with the endoplasmic reticulum and the nucleus, implying a role for Nox4 in regulation of both the cell cycle and protein synthesis. Consistent with this hypothesis, TGF-1 increased retinoblastoma protein phosphorylation at both Ser807/811 and Ser780. Silencing Nox4 prevented TGF-1-mediated retinoblastoma protein phosphorylation, proliferation, and cell hypertrophy. TGF-1 also increased phosphorylation of eukaryotic translation initiation factor 4E binding protein-1 at Thr37/46, and this was likewise blocked by silencing Nox4. This is the first report to suggest a functional role for Nox4 in cell cycle transition and to demonstrate that Nox4 influences the pathobiochemistry of asthma by generating reactive oxygen species that promote TGF-1-induced proliferation and hypertrophy of human airway smooth muscle.

Myc; cdc2; eukaryotic translation initiation factor 4E binding protein-1; nicotinamide adenine dinucleotide phosphate oxidase; reactive oxygen species; translation

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