Type I collagen is the major extracellular matrix protein in skin and other tissues. Excessive synthesis and deposition of collagen in the dermal region is the hallmark of skin fibrosis or scleroderma. The multifunctional cytokine transforming growth factor-beta (TGF-β) induces the Type I collagen synthesis and has been implicated in tissue fibrosis. The signal transducers Smads and transcriptional coactivators p300/ CBP are major regulators in the TGF-β-induced Type I collagen synthesis. In skin fibroblasts, p300 interacts with Smads and stimulates the Type I collagen synthesis. The intrinsic histone acetyltransferase activity of p300 is essential for maximal stimulation of collagen synthesis. The synthesis of Type I collagen is also negatively regulated by cytokines like interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α). While the profibrotic cytokine TGF-β induces the collagen synthesis, antifibrotic cytokines IFN-γ and TNF-α abrogate the TGF-β-induced collagen synthesis via activation of STAT1α or STAT1α-induced factor(s) and Jun family members respectively. The IFN-γ and TNF-α activated molecules compete with TGF-β signaling molecules Smads for limiting amount of cellular p300/CBP and suppress the TGF-β signaling. The transcriptional coactivators p300/CBP are known to interact with numerous transcription factors and play a pivotal role in the transcriptional regulation of numerous genes whose products control the cell cycle, growth and development. Post-translational modifications of p300/CBP by phosphorylation and/or methylation play a significant role in their functional activities. Abnormality in p300 or CBP activity has been implicated in different diseases, also known as 'Coactivators Diseases'. The present review discusses the significance of transcriptional coactivators p300/CBP in the cytokine modulation of extracellular matrix protein, Type I collagen synthesis, and its relevance to tissue fibrosis like scleroderma.
|Original language||English (US)|
|Number of pages||7|
|State||Published - Jul 25 2003|
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