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Fibroblast expression of the coactivator p300 governs the intensity of profibrotic response to transforming growth factor beta.
Arthritis Rheum. 2005 Apr; 52(4):1248-58.AR

Abstract

OBJECTIVE

Transforming growth factor beta (TGFbeta) induces profibrotic responses in normal fibroblasts, and plays a fundamental role in the pathogenesis of fibrosis in scleroderma (systemic sclerosis [SSc]). The intensity of cellular responses elicited by cytokines is modulated by transcriptional coactivators such as the histone acetylase p300. The objective of these studies was to delineate the physiologic role of p300 in Smad-dependent profibrotic responses elicited by TGFbeta.

METHODS

Ectopic p300 was transiently expressed in normal dermal fibroblasts. Cellular p300 levels were suppressed using p300-specific ribozymes. The regulation of gene expression was examined by transient transfection assays, Northern blotting, and immunoblot analysis. The expression of p300 in normal and scleroderma fibroblasts was evaluated by confocal microscopy and immunoblotting, and p300 levels in skin from mice with experimental scleroderma were assessed by immunohistochemistry.

RESULTS

In normal fibroblasts, TGFbeta induced an increase in the levels of p300. Forced expression of ectopic p300 in these cells dramatically enhanced the magnitude of TGFbeta responses, whereas selective depletion of p300 using ribozyme resulted in abrogation of TGFbeta-induced collagen synthesis and promoter activity. Furthermore, TGFbeta lost its ability to induce Smad-dependent transcription in p300-depleted fibroblasts. These responses could be fully rescued with ectopic p300. Abrogation of Smad-mediated TGFbeta signaling was not due to alterations in the levels or the ligand-dependent phosphorylation or intracellular trafficking of endogenous Smads. Immunohistochemical analysis demonstrated substantially increased p300 expression in lesional skin from mice with chronic graft-versus-host disease, an animal model of scleroderma. Furthermore, levels of p300 were 2-3-fold higher in cultured fibroblasts derived from SSc patients than in fibroblasts from matched normal controls.

CONCLUSION

These results establish, for the first time, that the coactivator histone acetylase p300, itself a target of TGFbeta regulation, is an essential component of the cellular TGFbeta signal transduction pathways mediating stimulation of collagen synthesis in fibroblasts. Since the cellular abundance of p300 appears to govern the intensity of profibrotic responses elicited by TGFbeta, elevated p300 expression in lesional tissue may contribute to the progression of skin fibrosis in scleroderma.

Authors+Show Affiliations

Northwestern University, Chicago, Illinois.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15818659

Citation

Bhattacharyya, Swati, et al. "Fibroblast Expression of the Coactivator P300 Governs the Intensity of Profibrotic Response to Transforming Growth Factor Beta." Arthritis and Rheumatism, vol. 52, no. 4, 2005, pp. 1248-58.
Bhattacharyya S, Ghosh AK, Pannu J, et al. Fibroblast expression of the coactivator p300 governs the intensity of profibrotic response to transforming growth factor beta. Arthritis Rheum. 2005;52(4):1248-58.
Bhattacharyya, S., Ghosh, A. K., Pannu, J., Mori, Y., Takagawa, S., Chen, G., Trojanowska, M., Gilliam, A. C., & Varga, J. (2005). Fibroblast expression of the coactivator p300 governs the intensity of profibrotic response to transforming growth factor beta. Arthritis and Rheumatism, 52(4), 1248-58.
Bhattacharyya S, et al. Fibroblast Expression of the Coactivator P300 Governs the Intensity of Profibrotic Response to Transforming Growth Factor Beta. Arthritis Rheum. 2005;52(4):1248-58. PubMed PMID: 15818659.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fibroblast expression of the coactivator p300 governs the intensity of profibrotic response to transforming growth factor beta. AU - Bhattacharyya,Swati, AU - Ghosh,Asish K, AU - Pannu,Jaspreet, AU - Mori,Yasuji, AU - Takagawa,Shinsuke, AU - Chen,Guofen, AU - Trojanowska,Maria, AU - Gilliam,Anita C, AU - Varga,John, PY - 2005/4/9/pubmed PY - 2005/5/13/medline PY - 2005/4/9/entrez SP - 1248 EP - 58 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 52 IS - 4 N2 - OBJECTIVE: Transforming growth factor beta (TGFbeta) induces profibrotic responses in normal fibroblasts, and plays a fundamental role in the pathogenesis of fibrosis in scleroderma (systemic sclerosis [SSc]). The intensity of cellular responses elicited by cytokines is modulated by transcriptional coactivators such as the histone acetylase p300. The objective of these studies was to delineate the physiologic role of p300 in Smad-dependent profibrotic responses elicited by TGFbeta. METHODS: Ectopic p300 was transiently expressed in normal dermal fibroblasts. Cellular p300 levels were suppressed using p300-specific ribozymes. The regulation of gene expression was examined by transient transfection assays, Northern blotting, and immunoblot analysis. The expression of p300 in normal and scleroderma fibroblasts was evaluated by confocal microscopy and immunoblotting, and p300 levels in skin from mice with experimental scleroderma were assessed by immunohistochemistry. RESULTS: In normal fibroblasts, TGFbeta induced an increase in the levels of p300. Forced expression of ectopic p300 in these cells dramatically enhanced the magnitude of TGFbeta responses, whereas selective depletion of p300 using ribozyme resulted in abrogation of TGFbeta-induced collagen synthesis and promoter activity. Furthermore, TGFbeta lost its ability to induce Smad-dependent transcription in p300-depleted fibroblasts. These responses could be fully rescued with ectopic p300. Abrogation of Smad-mediated TGFbeta signaling was not due to alterations in the levels or the ligand-dependent phosphorylation or intracellular trafficking of endogenous Smads. Immunohistochemical analysis demonstrated substantially increased p300 expression in lesional skin from mice with chronic graft-versus-host disease, an animal model of scleroderma. Furthermore, levels of p300 were 2-3-fold higher in cultured fibroblasts derived from SSc patients than in fibroblasts from matched normal controls. CONCLUSION: These results establish, for the first time, that the coactivator histone acetylase p300, itself a target of TGFbeta regulation, is an essential component of the cellular TGFbeta signal transduction pathways mediating stimulation of collagen synthesis in fibroblasts. Since the cellular abundance of p300 appears to govern the intensity of profibrotic responses elicited by TGFbeta, elevated p300 expression in lesional tissue may contribute to the progression of skin fibrosis in scleroderma. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/15818659/Fibroblast_expression_of_the_coactivator_p300_governs_the_intensity_of_profibrotic_response_to_transforming_growth_factor_beta_ L2 - https://doi.org/10.1002/art.20996 DB - PRIME DP - Unbound Medicine ER -