Barbara D. Smith
Professor of Biochemistry
Department of Biochemistry
Boston University School of Medicine
Silvio Conte Building, K123
Phone: 617-638-4159
Lab: 617-638-4222
Fax: 617-638-5339
Email: smith@biochem.bumc.bu.edu
Education
B.S, Simmons College, Boston, MA
M.A., Boston University, Boston, MA
Ph.D., Boston University, Boston, MA
People:
- Larry Luchsinger
- Anupma Agarwal
- Yedan Li
Research Interest
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 tumor formation, inflammation, atherosclerosis, and fibrosis. Collagen is a family of connective tissue proteins that plays a critical role in remodeling after injury or during tumorigenesis and development. 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 in collagen 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.
Representative publications
Sengupta, P.K. and Smith, B.D. Methylation in the initiation region of the first exon suppresses collagen pro-alpha2(I) gene transcription. Biochem Biophys Acta, 93183:1-15, 1998.
Sengupta, P.K. and Smith, B.D. A methylation responsive methylated DNA-binding protein/ Regulatory factor X MDBP/RFX site is in the exon of the collagen alpha2(I) gene. J. Biol Chem 274:36649-36655, 1999.
Stoddart, J.H., Harmon, M.H., Hou, F.X., Pritzker, C., Bronson, R., and Smith, B.D. Transgenic Mice with a Mutated alpha 1(I) Collagen Promoter have a Diminished Response to Bleomycin and Display Neurological Abnormalities. J. Cell Biochem 77:135-148, 2000.
Smith, B., Expression and Regulation of the Collagen Family in Skin, in Wound Healing and the Skin, Falanga, V., Ed., Martin Dunitz Limited, London, UK pg. 57-80, 2001.
Sun, W., Hou, F., Panchenko, M.P. and Smith, B.D. A member of the Y-box protein family interacts with an upstream element in the alpha1(I) collagen gene. Matrix Biology 20:527-541, 2001.
Sengupta, P. K. Fargo, J. and Smith, B.D. RFX family interacts at the collagen (COL1A2) start site and represses transcription. J. Biol. Chem. 277:24926-37, 2002.
Sengupta, S., Smith, E.M., Kim, K., Murnane, M. J., and Smith, B.D. DNA hypermethylation near the transcription start site of collagen alpha2(I) gene (COL1A2) occurs in both cancer cell lines and primary colorectal cancers. Cancer Research. 63:1789-1797, 2003.
Xu, Y, Wang, L. Buttice, G., Sengupta, P.K., and Smith, B.D. Interferon gamma repression of collagen (COL1A2) transcription is mediated by the RFX5 complex. J. Biol. Chem 278(49):49134-49144, 2003.
Xu, Y, Wang, L. Buttice, G., Sengupta, P.K., and Smith, B.D. Major histocompatibility class II transactivator (CIITA) mediates repression of collagen (COL1A2) transcription by interferon gamma. J. Biol. Chem 279(40): 41319-41332 2004.
Sengupta P., Xu Y., Wang L., Widom R., Smith B.D. Collagen alpha1(I) Gene (COL1A1) is Repressed by RFX Family. J Biol Chem, 280, 21004-21014, 2005.
Butticè, G.,Miller, J., Wang, L., and Smith, B. D. Interferon-gamma induces major histocompatibility (MHC) Class II transactivator (CIITA) that mediates collagen repression and MHC II activation by human aortic smooth muscle cells. Circ Res, 98(4):472-9 Epub Jan 26, 2006.
Sengupta, P.K., Seto E., and Smith, B.D. RFX family proteins differentially interact with HDACs to repress collagen alpha 2(I) gene (COL1A2) expression. J. Biol. Chem. 281(14):9260-9270.Epub Feb 6, 2006.
Xu Y, McDonald J, Perloff E, Buttice G, Schreiber BM, Smith BD. Collagen and major histocompatibility class II expression in mesenchymal cells from CIITA hypomorphic mice. Mol Immunol., 44, 1720-32, 2007.
Xu Y, Farmer SR, Smith BD. PPARgamma interacts with CIITA/RFX5 complex to repress type I collagen gene expression. J Biol Chem , 282(36):26046-56. Epub. Jul 3, 2007.
Xu, Y, Harton J, and Smith B.D. CIITA mediates IFN-gamma repression of collagen transcription through phosphorylation dependent interactions with co-repressor molecules. J. Biol. Chem 282, 26046-26056, 2008.
Xu ,Y., Ravid, K., and Smith B.D. 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, 2008. PMCID: PMC2386913
