Nox4 mediates TGF-beta1-induced retinoblastoma protein phosphorylation, proliferation, and hypertrophy in human airway smooth muscle cells.

Abstract

Transforming growth factor-beta1 (TGF-beta1) 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-beta1 have not been fully elucidated. In this study, we demonstrate that TGF-beta1 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-beta1-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-beta1 increased retinoblastoma protein phosphorylation at both Ser807/811 and Ser780. Silencing Nox4 prevented TGF-beta1-mediated retinoblastoma protein phosphorylation, proliferation, and cell hypertrophy. TGF-beta1 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-beta1-induced proliferation and hypertrophy of human airway smooth muscle.

• Authors: Anne Sturrock, Thomas P Huecksteadt, Kimberly Norman, Karl Sanders, Thomas M Murphy, Pasquale Chitano, Kimberly Wilson, John R Hoidal, Thomas P Kennedy
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 292 Issue 6 Pg. L1543-55 (Jun 2007) ISSN: 1040-0605 [Print] United States
• PMID: 17369289 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Eukaryotic Initiation Factor-4E
• Proto-Oncogene Proteins c-myc
• Reactive Oxygen Species
• Retinoblastoma Protein
• SMAD3 protein, human
• Smad3 Protein
• Transforming Growth Factor beta1
• activin A
• Activins
• NADPH Oxidase 4
• NADPH Oxidases
• NOX4 protein, human
• Phosphatidylinositol 3-Kinases
• CDC2 Protein Kinase

Topics

• Activins (metabolism, pharmacology)
• Asthma (metabolism, pathology)
• Bronchi (cytology)
• CDC2 Protein Kinase (metabolism)
• Cell Division (drug effects, physiology)
• Cell Nucleus (enzymology)
• Cells, Cultured
• Eukaryotic Initiation Factor-4E (metabolism)
• Humans
• Hypertrophy
• Myocytes, Smooth Muscle (cytology, drug effects, enzymology)
• NADPH Oxidase 4
• NADPH Oxidases (genetics, metabolism)
• Oxidation-Reduction
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Protein Biosynthesis (physiology)
• Proto-Oncogene Proteins c-myc (metabolism)
• Reactive Oxygen Species (metabolism)
• Retinoblastoma Protein (metabolism)
• Signal Transduction (drug effects, physiology)
• Smad3 Protein (metabolism)
• Transfection
• Transforming Growth Factor beta1 (metabolism, pharmacology)