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Regulator of Cell Cycle Protein (RGCC/RGC-32) Protects against Pulmonary Fibrosis.
- Source :
-
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2022 Feb; Vol. 66 (2), pp. 146-157. - Publication Year :
- 2022
-
Abstract
- Some previous studies in tissue fibrosis have suggested a profibrotic contribution from elevated expression of a protein termed either RGCC (regulator of cell cycle) or RGC-32 (response gene to complement 32 protein). Our analysis of public gene expression datasets, by contrast, revealed a consistent decrease in RGCC mRNA levels in association with pulmonary fibrosis. Consistent with this observation, we found that stimulating primary adult human lung fibroblasts with transforming growth factor (TGF)-β in cell cultures elevated collagen expression and simultaneously attenuated RGCC mRNA and protein levels. Moreover, overexpression of RGCC in cultured lung fibroblasts attenuated the stimulating effect of TGF-β on collagen levels. Similar to humans with pulmonary fibrosis, the levels of RGCC were also decreased in vivo in lung tissues of wild-type mice challenged with bleomycin in both acute and chronic models. Mice with constitutive RGCC gene deletion accumulated more collagen in their lungs in response to chronic bleomycin challenge than did wild-type mice. RNA-Seq analyses of lung fibroblasts revealed that RGCC overexpression alone had a modest transcriptomic effect, but in combination with TGF-β stimulation, induced notable transcriptomic changes that negated the effects of TGF-β, including on extracellular matrix-related genes. At the level of intracellular signaling, RGCC overexpression delayed early TGF-β-induced Smad2/3 phosphorylation, elevated the expression of total and phosphorylated antifibrotic mediator STAT1, and attenuated the expression of a profibrotic mediator STAT3. We conclude that RGCC plays a protective role in pulmonary fibrosis and that its decline permits collagen accumulation. Restoration of RGCC expression may have therapeutic potential in pulmonary fibrosis.
- Subjects :
- Animals
Cell Cycle
Cells, Cultured
Female
Fibroblasts pathology
Humans
Lung pathology
Mice
Mice, Inbred C57BL
Phosphorylation
Pulmonary Fibrosis etiology
Pulmonary Fibrosis metabolism
Pulmonary Fibrosis pathology
Smad2 Protein genetics
Transcriptome
Transforming Growth Factor beta3 genetics
Fibroblasts metabolism
Lung metabolism
Nuclear Proteins physiology
Pulmonary Fibrosis prevention & control
Smad2 Protein metabolism
Transforming Growth Factor beta3 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4989
- Volume :
- 66
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of respiratory cell and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 34668840
- Full Text :
- https://doi.org/10.1165/rcmb.2021-0022OC