Caveolin-1 increases basal and TGF-beta1-induced expression of type I procollagen through PI-3 kinase/Akt/mTOR pathway in human dermal fibroblasts.
Caveolin-1 (Cav-1) is a major structural protein of caveolae and plays an important role as a negative regulator of various signaling pathways such as the transforming growth factor-beta (TGF-beta)/smad pathway. In this study, we investigated the role of cav-1 on basal and TGF-beta1-induced expression of type I procollagen in human dermal fibroblasts. Our results demonstrated that basal and TGF-beta1-induced expression of type I procollagen were significantly increased by adenoviral cav-1 (Ad-cav-1) overexpression, while the basal level of type I procollagen was decreased by cav-1 siRNA. Overexpression of cav-1 inhibited TGF-beta1-induced phosphorylation of smad3 and transcription of 3TP-Lux and SBE luciferase reporters, suggesting that cav-1 may inhibit the TGF-beta1/smad signaling pathway. We observed that TGF-beta1-induced type I procollagen expression was decreased by smad3 siRNA transfection. However, the reduction of TGF-beta1-induced type I procollagen expression by smad3 siRNA was reversed by cav-1 overexpression. In addition, our results also showed that TGF-beta1 treatment increased the phosphorylation of Akt, and Ad-cav-1 infection augmented this TGF-beta1-induced phosphorylation of Akt. Ad-myr-Akt infection significantly increased the basal expression of type I procollagen. In contrast, TGF-beta1-induced type I procollagen expression was decreased by Akt siRNA transfection and the PI3-kinase inhibitor, LY294002, inhibited the TGF-beta1-induced type I procollagen expression and also inhibited the cav-1-induced expression of type I procollagen. In conclusion, our results suggest that cav-1 increases the basal and TGF-beta1-induced expression of type I procollagen by regulating two opposite signaling pathways: inhibiting TGF-beta1/smad signaling and activating a PI-3 kinase/Akt/mTOR-dependent pathway in human dermal fibroblasts, ultimately resulting in increased type I procollagen expression.
Kim
Sangmin
S
Department of Dermatology, Seoul National University College of Medicine, Republic of Korea.
Lee
Youngae
Y
Seo
Jo Eun
JE
Cho
Kwang Hyun
KH
Chung
Jin Ho
JH
D000256:Adenoviridae; D000328:Adult; D051242:Caveolin 1 / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism*; D020405:Dermis / Q000166:cytology / Q000201:enzymology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D051900:Smad3 Protein / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
D051242:Caveolin 1; D024042:Collagen Type I; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D020123:Sirolimus; D051900:Smad3 Protein; D058570:TOR Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1; C546842:MTOR protein, human