Barbara D. Smith
Boston University School of Medicine
BS, Simmons College, Boston, MA
MA, Boston University, Boston, MA
PhD, Boston University, Boston, MA
The primary goal in this laboratory is to establish a better understanding of the mechanisms involved in the control of collagen gene expression associated with inflammation, atherosclerosis, tumors, and fibrotic diseases including systemic sclerosis. Collagen, a family of extracellular proteins, plays a critical role in remodeling after injury. Progressive deposition of excess extracellular matrix (ECM), occurs in a large group of diseases with no effective therapy including cardiovascular disease, pulmonary fibrosis, diabetic nephropathy, systemic sclerosis, and liver cirrhosis. Fibrosis (excessive scarring) is a progressive deposition of excess collagen-rich extracellular matrix produced by activated myofibroblasts leading to impairment and finally failure of affected organs. In normal healing following injury, fibroblasts differentiate into myofibroblasts. If progression to fibrosis occurs, these myofibroblasts do not undergo apoptosis but instead continue to proliferate and produce excess amounts of ECM. Isolated primary fibroblasts from fibrotic lesions maintain their activated myofibroblast phenotype containing abundant stress fibers with smooth muscle actin (SMA). Myocardin related transcription factors (MRTF-A, MRTF-B), members of the myocardin family, link actin dynamics with gene transcription. Our data indicate that MRTF-A dramatically (100 fold) activates collagen transcription. Fibroblasts with knockdown of MRTFA have different morphology and produce less collagen and SMA. We hypothesize that MRTFA plays a central role in activation and perpetuation of myofibroblast during the development of fibrotic disease.
Our laboratory has been examining both activation and repression of collagen transcription using molecular biology approaches. We have demonstrated that collagen type I genes are methylated in the first exon in cancer cells and colon cancer. Collagen gene is silenced in certain tumors. A methylation sensitive DNA binding protein (RFX1) represses transcription by binding to the collagen gene transcription start site. This protein belongs to a family of proteins that can function as transcription activators or repressors. RFX1 interacts with a co-repressor complex containing histone deacetylase which could be involved with spreading of DNA methylation and silencing. A RFX5 complex containing three other proteins (RFXANK/B, RFXAP, CIITA) are essential activators of major histocompatibility complex class II (MHC II) proteins that respond to interferon-gamma during inflammation and activate cells to become antigen producing cells. Interferon activates RFX5/CIITA synthesis and nuclear localization in human fibroblasts and smooth muscle cells. RFX5 proteins form a complex at the RFX site at the collagen gene transcription start site and recruits CIITA to repress collagen transcription through a phosphorylation sensitive interaction with co-repressor complex. Thus, this family of proteins may be very important modulators of collagen expression during inflammation.
- Shiwen X, Stratton R, Nikitorowicz-Buniak J, Ahmed-Abdi B, Ponticos M, Denton C, Abraham D, Takahashi A, Suki B, Layne MD, Lafyatis R, Smith BD. A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis. PLoS One. 2015; 10(5):e0126015.View in: PubMed
- Myocardin-Related Transcription Factor A Regulates Conversion of Progenitors to Beige Adipocytes. McDonald ME, Li C, Bian H, Smith BD, Layne MD, Farmer SR. Cell. 2015 Jan 7. pii: S0092-8674(14)01575-X. doi: 10.1016/j.cell.2014.12.005. [Epub ahead of print]
- Aortic carboxypeptidase-like protein (ACLP) enhances lung myofibroblast differentiation through transforming growth factor β receptor-dependent and -independent pathways. Tumelty KE, Smith BD, Nugent MA, Layne MD. J Biol Chem. 2014 Jan 31;289(5):2526-36.
- Luchsinger LL, Patenaude CA, Smith BD, Layne MD. Myocardin Related Transcription Factor-A Complexes Activate Type I Collagen Expression in Lung Fibroblasts. J Biol Chem 2011. 286(51) 44116-44125.
- Wu X, Kong X, Luchsinger L, Smith BD, Xu Y. (2009) Regulating the activity of class II transactivator by posttranslational modifications: exploring the possibilities. Mol Cell Biol, 29, 5639-44.
- Xu Y, Ravid K, Smith BD. (2008) Major histocompatibility class II transactivator (CIITA) expression in smooth muscle cells from A2b adenosine receptor knockout mice: crosstalk between the adenosine and IFN-gamma signaling. J Biol Chem, 283, 14213-20.
- Xu Y, Harton JA, Smith BD. (2008) CIITA mediates interferon-gamma repression of collagen transcription through phosphorylation-dependent interactions with co-repressor molecules. J Biol Chem, 283, 1243-56.
- Xu Y, Farmer SR, Smith BD. (2007) Peroxisome proliferator-activated receptor gamma interacts with CIITA/RFX5 complex to repress type I collagen gene expression. J Biol Chem, 282, 26046-56.
- Xu Y, McDonald J, Perloff E, Buttice G, Schreiber BM, Smith BD. (2007) Collagen and major histocompatibility class II expression in mesenchymal cells from CIITA hypomorphic mice. Mol Immunol, 44, 1720-32.
- Xu Y, Sengupta PK, Seto E, Smith BD. (2006) RFX family proteins differentially interact with HDACs to repress collagen alpha 2(I) gene (COL1A2) expression. J Biol Chem, 281, 9260-70.
- Buttice G, Miller J, Wang L, Smith BD. (2006) Interferon-gamma induces major histocompatibility class II transactivator (CIITA), which mediates collagen repression and major histocompatibility class II activation by human aortic smooth muscle cells. Circ Res, 98, 472-8.
- Sengupta P, Xu Y, Wang L, Widom R, Smith BD. (2005) Collagen alpha1(I) Gene (COL1A1) is Repressed by RFX Family. J Biol Chem, 280, 21004-21014.
- Xu Y, Wang L, Buttice G, Sengupta PK, Smith BD. (2004) Major Histocompatibility Class II Transactivator (CIITA) Mediates Repression of Collagen (COL1A2) Transcription by Interferon gamma (IFN-gamma). J Biol Chem, 279, 41319-41332.
- Xu Y, Wang L, Buttice G, Sengupta PK, Smith BD. (2003) Interferon gamma repression of collagen (COL1A2) transcription is mediated by the RFX5 complex. J Biol Chem, 278, 49134-44.
- Sengupta S, Smith EM, Kim K, Murnane MJ, Smith BD. (2003) DNA hypermethylation near the transcription start site of collagen alpha2(I) gene (COL1A2) occurs in both cancer cell lines and primary colorectal cancers . Cancer Res, 63, 1789-97.