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      p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-β: epigenetic feed-forward amplification of fibrosis


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          Fibrosis, the hallmark of systemic sclerosis (SSc), is characterized by persistent fibroblast activation triggered by transforming growth factor-β (TGF-β). Since the acetyltransferase p300 plays a key role in fibrosis and its availability governs the intensity of fibrotic responses, we investigated p300 expression in SSc and the molecular basis of its regulation. We found that expression of p300 was markedly elevated in SSc skin biopsies, and was induced by TGF-β in explanted normal skin fibroblasts. Stimulation of p300 by TGF-β was independent of Smads, and involved the early-immediate transcription factor Egr-1, a key regulator of profibrotic TGF-β signaling. Indeed, Egr-1 was both sufficient and necessary for p300 regulation in vitro and in vivo. Increased p300 accumulation in TGF-β-treated fibroblasts was associated with histone hyperacetylation, whereas p300 depletion, or selective pharmacological blockade of its acetyltransferase activity, attenuated TGF-β-induced responses. Moreover, TGF-β enhanced both p300 recruitment and in vivo histone H4 acetylation at the COL1A2 locus. These findings implicate p300-mediated histone acetylation as a fundamental epigenetic mechanism in fibrogenesis, and place Egr-1 upstream in TGF-β-driven stimulation of p300 gene expression. The results establish a firm link between fibrosis with aberrant p300 expression and epigenetic activity to our knowledge previously unreported. Targeted disruption of p300-mediated histone acetylation might therefore represent a viable anti-fibrotic strategy.

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          CBP/p300 in cell growth, transformation, and development.

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            Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.

            The Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome with facial abnormalities, broad thumbs, broad big toes and mental retardation as the main clinical features. Many patients with RTS have been shown to have breakpoints in, and microdeletions of, chromosome 16p13.3 (refs 4-8). Here we report that all these breakpoints are restricted to a region that contains the gene for the human CREB binding protein (CBP), a nuclear protein participating as a co-activator in cyclic-AMP-regulated gene expression. We show that RTS results not only from gross chromosomal rearrangements of chromosome 16p, but also from point mutations in the CBP gene itself. Because the patients are heterozygous for the mutations, we propose that the loss of one functional copy of the CBP gene underlies the developmental abnormalities in RTS and possibly the propensity for malignancy.
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              p300/CBP and cancer.

              p300 and cyclic AMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a number of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematological disorders. p300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in critical protein domains, and these are often associated with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematological tumor formation. The involvement of these proteins in critical tumorigenic pathways (including TGF-beta, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.

                Author and article information

                J Invest Dermatol
                J. Invest. Dermatol.
                The Journal of investigative dermatology
                4 December 2012
                10 January 2013
                May 2013
                01 November 2013
                : 133
                : 5
                : 1302-1310
                [1 ]Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL
                [2 ]Boston University, Boston, MA
                [3 ]Department of Biochemistry and Molecular Cell Biology, SJTU-SM, Shanghai, China
                [4 ]Department of Microbiology and Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL
                Author notes
                [* ]Address for correspondence: Northwestern University Feinberg School of Medicine, Division of Rheumatology, 240 East Huron Street, Chicago, Illinois 60611. Tel: (312) 503-0368. Fax: (312) 503-0994. j-varga@ 123456northwestern.edu or jun-wei@ 123456northwestern.edu

                Present address: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois 60611 .

                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: R01 AR042309 || AR

                acetyltransferase p300,tgf-β,fibroblast,systemic sclerosis,fibrosis,egr-1,epigenetics
                acetyltransferase p300, tgf-β, fibroblast, systemic sclerosis, fibrosis, egr-1, epigenetics


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