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1-Induced Retinoblastoma Protein Phosphorylation, Proliferation and Hypertrophy in Human Airway Smooth Muscle Cells
1 Internal Medicine, University of Utah Medical Center, Salt Lake City, Utah, United States
2 Department of Internal Medicine, Division of Respiratory, Critical Care, and Occupational Medicine, VA Salt Lake City Health Care System and University of Utah Health Sciences Center, Salt Lake City, United States
3 Pediatrics, Duke University Medical Center, Durham, North Carolina, United States
4 Biology, Winthrop University, Rock Hill, South Carolina, United States
5 Internal Medicine, University of Utah, Salt Lake City, Utah, United States
6 Division of Pulmonary, Critical Care and Occupational (Pulmonary) Medicine, University of Utah, Salt Lake City, Utah, United States
* To whom correspondence should be addressed. E-mail: thomas.kennedy{at}hsc.utah.edu.
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 non-phagocyte NAD(P)H oxidase catalytic homologue 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 to 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 serine 807/811 and serine 780. 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 threonines 37/46, and this was also blocked by silencing Nox4. This is the first report to suggest a functional role for Nox4 in cell cycle transition and to demonstrate a central function for Nox4 in the pathobiochemistry of asthma by generating reactive oxygen species that mediate TGF-1-induced proliferation and hypertrophy of human airway smooth muscle.
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