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Involvement of the constitutive complex formation of c-Ski/SnoN with Smads in the impaired negative feedback regulation of transforming growth factor beta signaling in scleroderma fibroblasts.
Arthritis Rheum. 2007 May; 56(5):1694-705.AR

Abstract

OBJECTIVE

The principal effect of transforming growth factor beta1 (TGFbeta1) on mesenchymal cells is its stimulation of extracellular matrix synthesis. Previous reports indicated the significance of the autocrine TGFbeta loop in the pathogenesis of scleroderma. The aim of this study was to examine c-Ski and SnoN, principal molecules in the negative regulation of TGFbeta signaling, to further understand the autocrine TGFbeta loop in scleroderma.

METHODS

Levels of expression of c-Ski/SnoN on cultured normal and scleroderma fibroblasts were determined by Western blotting, Northern blotting, and immunohistochemical staining. To determine the protein-protein interaction between c-Ski/SnoN, Smads, and p300, immunoprecipitation was performed. A transient transfection assay was performed to measure promoter activity of the alpha2(I) collagen gene and the 3TP-Lux plasmid construct.

RESULTS

Scleroderma fibroblasts exhibited increased c-Ski/SnoN levels compared with normal fibroblasts, both in vivo and in vitro. Although c-Ski/SnoN constitutively formed a complex with Smads by immunoprecipitation, the inhibitory effect of c-Ski/SnoN on the promoter activity of human alpha2(I) collagen and 3TP-Lux was impaired in scleroderma fibroblasts. Immunoprecipitation analyses also revealed that overexpressed c-Ski/SnoN could not compete with p300 in these cells.

CONCLUSION

These results indicate that impaired competition with p300 is the possible cause of dysfunction of c-Ski/SnoN in scleroderma fibroblasts and that this might contribute to maintenance of the autocrine TGFbeta loop in this disease.

Authors+Show Affiliations

University of Tokyo, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17469184

Citation

Jinnin, Masatoshi, et al. "Involvement of the Constitutive Complex Formation of c-Ski/SnoN With Smads in the Impaired Negative Feedback Regulation of Transforming Growth Factor Beta Signaling in Scleroderma Fibroblasts." Arthritis and Rheumatism, vol. 56, no. 5, 2007, pp. 1694-705.
Jinnin M, Ihn H, Mimura Y, et al. Involvement of the constitutive complex formation of c-Ski/SnoN with Smads in the impaired negative feedback regulation of transforming growth factor beta signaling in scleroderma fibroblasts. Arthritis Rheum. 2007;56(5):1694-705.
Jinnin, M., Ihn, H., Mimura, Y., Asano, Y., & Tamaki, K. (2007). Involvement of the constitutive complex formation of c-Ski/SnoN with Smads in the impaired negative feedback regulation of transforming growth factor beta signaling in scleroderma fibroblasts. Arthritis and Rheumatism, 56(5), 1694-705.
Jinnin M, et al. Involvement of the Constitutive Complex Formation of c-Ski/SnoN With Smads in the Impaired Negative Feedback Regulation of Transforming Growth Factor Beta Signaling in Scleroderma Fibroblasts. Arthritis Rheum. 2007;56(5):1694-705. PubMed PMID: 17469184.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of the constitutive complex formation of c-Ski/SnoN with Smads in the impaired negative feedback regulation of transforming growth factor beta signaling in scleroderma fibroblasts. AU - Jinnin,Masatoshi, AU - Ihn,Hironobu, AU - Mimura,Yoshihiro, AU - Asano,Yoshihide, AU - Tamaki,Kunihiko, PY - 2007/5/1/pubmed PY - 2007/6/20/medline PY - 2007/5/1/entrez SP - 1694 EP - 705 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 56 IS - 5 N2 - OBJECTIVE: The principal effect of transforming growth factor beta1 (TGFbeta1) on mesenchymal cells is its stimulation of extracellular matrix synthesis. Previous reports indicated the significance of the autocrine TGFbeta loop in the pathogenesis of scleroderma. The aim of this study was to examine c-Ski and SnoN, principal molecules in the negative regulation of TGFbeta signaling, to further understand the autocrine TGFbeta loop in scleroderma. METHODS: Levels of expression of c-Ski/SnoN on cultured normal and scleroderma fibroblasts were determined by Western blotting, Northern blotting, and immunohistochemical staining. To determine the protein-protein interaction between c-Ski/SnoN, Smads, and p300, immunoprecipitation was performed. A transient transfection assay was performed to measure promoter activity of the alpha2(I) collagen gene and the 3TP-Lux plasmid construct. RESULTS: Scleroderma fibroblasts exhibited increased c-Ski/SnoN levels compared with normal fibroblasts, both in vivo and in vitro. Although c-Ski/SnoN constitutively formed a complex with Smads by immunoprecipitation, the inhibitory effect of c-Ski/SnoN on the promoter activity of human alpha2(I) collagen and 3TP-Lux was impaired in scleroderma fibroblasts. Immunoprecipitation analyses also revealed that overexpressed c-Ski/SnoN could not compete with p300 in these cells. CONCLUSION: These results indicate that impaired competition with p300 is the possible cause of dysfunction of c-Ski/SnoN in scleroderma fibroblasts and that this might contribute to maintenance of the autocrine TGFbeta loop in this disease. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/17469184/Involvement_of_the_constitutive_complex_formation_of_c_Ski/SnoN_with_Smads_in_the_impaired_negative_feedback_regulation_of_transforming_growth_factor_beta_signaling_in_scleroderma_fibroblasts_ L2 - https://doi.org/10.1002/art.22588 DB - PRIME DP - Unbound Medicine ER -