Keywords
Last Name

Barbara D. Smith, PhD

TitleProfessor
InstitutionBoston University School of Medicine
DepartmentBiochemistry
Address72 E. Concord St Silvio Conte (K)
Boston MA 02118
Phone(617) 638-4159
ORCID ORCID Icon0000-0002-5375-7627
Other Positions
TitleGraduate Faculty (Primary Mentor of Grad Students)
InstitutionBoston University School of Medicine, Graduate Medical Sciences

 Research Expertise & Professional Interests
The primary goal in our 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.

 NIH RePORTER Grants
 Self-Described Keywords
  • Biochemistry
  • Collagen
  • DNA methylation
  • Extracellular matrix
  • fibroblasts
  • growth factors
  • interferon gamma
  • Molecular Biology
  • myocardin family
  • TGF-beta
  • transcription factors
 Publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
List All   |   Timeline
  1. Ponticos, M., and B.D. Smith. Journal of biomedical research. Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis. 2014; 28(1):25-39..
  2. Tumelty KE, Smith BD, Nugent MA, Layne MD. Aortic Carboxypeptidase-like Protein (ACLP) Enhances Lung Myofibroblast Differentiation through Transforming Growth Factor ß Receptor-dependent and -independent Pathways. J Biol Chem. 2014 Jan 31; 289(5):2526-36.
    View in: PubMed
  3. Ponticos M, Smith BD. Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis. J Biomed Res. 2014 Jan; 28(1):25-39.
    View in: PubMed
  4. 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 Dec 23; 286(51):44116-25.
    View in: PubMed
  5. Xu Y, Luchsinger L, Lucey EC, Smith BD. The effect of class II transactivator mutations on bleomycin-induced lung inflammation and fibrosis. Am J Respir Cell Mol Biol. 2011 Jun; 44(6):898-905.
    View in: PubMed
  6. Wu X, Kong X, Luchsinger L, Smith BD, Xu Y. Regulating the activity of class II transactivator by posttranslational modifications: exploring the possibilities. Mol Cell Biol. 2009 Nov; 29(21):5639-44.
    View in: PubMed
  7. St Hilaire C, Koupenova M, Carroll SH, Smith BD, Ravid K. TNF-alpha upregulates the A2B adenosine receptor gene: The role of NAD(P)H oxidase 4. Biochem Biophys Res Commun. 2008 Oct 24; 375(3):292-6.
    View in: PubMed
  8. Xu Y, Ravid K, Smith BD. Major histocompatibility class II transactivator expression in smooth muscle cells from A2b adenosine receptor knock-out mice: cross-talk between the adenosine and interferon-gamma signaling. J Biol Chem. 2008 May 23; 283(21):14213-20.
    View in: PubMed
  9. Xu Y, Harton JA, Smith BD. CIITA mediates interferon-gamma repression of collagen transcription through phosphorylation-dependent interactions with co-repressor molecules. J Biol Chem. 2008 Jan 18; 283(3):1243-56.
    View in: PubMed
  10. Xu Y, Farmer SR, Smith BD. Peroxisome proliferator-activated receptor gamma interacts with CIITA x RFX5 complex to repress type I collagen gene expression. J Biol Chem. 2007 Sep 7; 282(36):26046-56.
    View in: PubMed
  11. Xu Y, McDonald J, Perloff E, Butticè G, Schreiber BM, Smith BD. Collagen and major histocompatibility class II expression in mesenchymal cells from CIITA hypomorphic mice. Mol Immunol. 2007 Mar; 44(7):1709-21.
    View in: PubMed
  12. Xu Y, Sengupta PK, Seto E, Smith BD. Regulatory factor for X-box family proteins differentially interact with histone deacetylases to repress collagen alpha2(I) gene (COL1A2) expression. J Biol Chem. 2006 Apr 7; 281(14):9260-70.
    View in: PubMed
  13. Butticè G, Miller J, Wang L, Smith BD. 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. 2006 Mar 3; 98(4):472-9.
    View in: PubMed
  14. Sengupta P, Xu Y, Wang L, Widom R, Smith BD. Collagen alpha1(I) gene (COL1A1) is repressed by RFX family. J Biol Chem. 2005 Jun 3; 280(22):21004-14.
    View in: PubMed
  15. Xu Y, Wang L, Butticè G, Sengupta PK, Smith BD. Major histocompatibility class II transactivator (CIITA) mediates repression of collagen (COL1A2) transcription by interferon gamma (IFN-gamma). J Biol Chem. 2004 Oct 1; 279(40):41319-32.
    View in: PubMed
  16. Xu Y, Wang L, Buttice G, Sengupta PK, Smith BD. Interferon gamma repression of collagen (COL1A2) transcription is mediated by the RFX5 complex. J Biol Chem. 2003 Dec 5; 278(49):49134-44.
    View in: PubMed
  17. Sengupta PK, Smith EM, Kim K, Murnane MJ, Smith BD. DNA hypermethylation near the transcription start site of collagen alpha2(I) gene occurs in both cancer cell lines and primary colorectal cancers. Cancer Res. 2003 Apr 15; 63(8):1789-97.
    View in: PubMed
  18. Sengupta PK, Fargo J, Smith BD. The RFX family interacts at the collagen (COL1A2) start site and represses transcription. J Biol Chem. 2002 Jul 12; 277(28):24926-37.
    View in: PubMed
  19. Sun W, Hou F, Panchenko MP, Smith BD. A member of the Y-box protein family interacts with an upstream element in the alpha1(I) collagen gene. Matrix Biol. 2001 Dec; 20(8):527-41.
    View in: PubMed
  20. 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. 2001; 57-80.
  21. Stoddart JH, Ladd D, Bronson RT, Harmon M, Jaworski J, Pritzker C, Lausen N, Smith BD. Transgenic mice with a mutated collagen promoter display normal response during bleomycin-induced fibrosis and possess neurological abnormalities. J Cell Biochem. 2000 Feb; 77(1):135-48.
    View in: PubMed
  22. Sengupta PK, Ehrlich M, Smith BD. A methylation-responsive MDBP/RFX site is in the first exon of the collagen alpha2(I) promoter. J Biol Chem. 1999 Dec 17; 274(51):36649-55.
    View in: PubMed
  23. Sengupta PK, Smith BD. Methylation in the initiation region of the first exon suppresses collagen pro-alpha2(I) gene transcription. Biochim Biophys Acta. 1998 Nov 26; 1443(1-2):75-89.
    View in: PubMed
  24. Doyle SA, Smith BD. Role of the pro-alpha2(I) COOH-terminal region in assembly of type I collagen: disruption of two intramolecular disulfide bonds in pro-alpha2(I) blocks assembly of type I collagen. J Cell Biochem. 1998 Nov 1; 71(2):233-42.
    View in: PubMed
  25. Lim AL, Doyle SA, Balian G, Smith BD. Role of the pro-alpha2(I) COOH-terminal region in assembly of type I collagen: truncation of the last 10 amino acid residues of pro-alpha2(I) chain prevents assembly of type I collagen heterotrimer. J Cell Biochem. 1998 Nov 1; 71(2):216-32.
    View in: PubMed
  26. Agarwal AR, Goldstein RH, Lucey E, Ngo HQ, Smith BD. Cell-specific expression of the alpha 1 (I) collagen promoter-CAT transgene in skin and lung: a response to TGF-beta subcutaneous injection and bleomycin endotracheal instillation. J Cell Biochem. 1996 Nov 1; 63(2):135-48.
    View in: PubMed
  27. Lucey EC, Ngo HQ, Agarwal A, Smith BD, Snider GL, Goldstein RH. Differential expression of elastin and alpha 1(I) collagen mRNA in mice with bleomycin-induced pulmonary fibrosis. Lab Invest. 1996 Jan; 74(1):12-20.
    View in: PubMed
  28. Fine A, Panchenko MP, Smith BD, Yu Q, Goldstein RH. Discordant regulation of transforming growth factor-beta receptors by prostaglandin E2. Biochim Biophys Acta. 1995 Mar 14; 1261(1):19-24.
    View in: PubMed
  29. Moreland RB, Traish A, McMillin MA, Smith B, Goldstein I, Saenz de Tejada I. PGE1 suppresses the induction of collagen synthesis by transforming growth factor-beta 1 in human corpus cavernosum smooth muscle. J Urol. 1995 Mar; 153(3 Pt 1):826-34.
    View in: PubMed
  30. Lim A, Greenspan DS, Smith BD. Expression of alpha 2 type I collagen in W8 cells increases cell adhesion and decreases colony formation in soft agar. Matrix Biol. 1994 Jan; 14(1):21-30.
    View in: PubMed
  31. Ritzenthaler JD, Goldstein RH, Fine A, Smith BD. Regulation of the alpha 1(I) collagen promoter via a transforming growth factor-beta activation element. J Biol Chem. 1993 Jun 25; 268(18):13625-31.
    View in: PubMed
  32. Minto AW, Fogel MA, Natori Y, O'Meara YM, Abrahamson DR, Smith B, Salant DJ. Expression of type I collagen mRNA in glomeruli of rats with passive Heymann nephritis. Kidney Int. 1993 Jan; 43(1):121-7.
    View in: PubMed
  33. Guenette DK, Ritzenthaler JD, Foley J, Jackson JD, Smith BD. DNA methylation inhibits transcription of procollagen alpha 2(I) promoters. Biochem J. 1992 May 1; 283 ( Pt 3):699-703.
    View in: PubMed
  34. Fine A, Matsui R, Zhan X, Poliks CF, Smith BD, Goldstein RH. Discordant regulation of human type I collagen genes by prostaglandin E2. Biochim Biophys Acta. 1992 Apr 30; 1135(1):67-72.
    View in: PubMed
  35. Ritzenthaler JD, Goldstein RH, Fine A, Lichtler A, Rowe DW, Smith BD. Transforming-growth-factor-beta activation elements in the distal promoter regions of the rat alpha 1 type I collagen gene. Biochem J. 1991 Nov 15; 280 ( Pt 1):157-62.
    View in: PubMed
  36. Fine A, Poliks CF, Smith BD, Goldstein RH. The accumulation of type I collagen mRNAs in human embryonic lung fibroblasts stimulated by transforming growth factor-beta. Connect Tissue Res. 1990; 24(3-4):237-47.
    View in: PubMed
  37. Smith BD. Mechanisms for non-coordinate expression of type 1 collagen alpha chains. In: Structure, Molecular biology and pathology of collagen. Annals NY Acad Sci. 1990; 580:459-461.
  38. Baldwin CT, Silbert JE, Humphries DE, Cogburn JN, Smith BD. Increased proteoglycan synthesis following the differentiation of F9 embryonal carcinoma cells: formation of a differentiation-specific proteoheparan sulfate. Matrix. 1989 Nov; 9(5):389-96.
    View in: PubMed
  39. Fine A, Poliks CF, Donahue LP, Smith BD, Goldstein RH. The differential effect of prostaglandin E2 on transforming growth factor-beta and insulin-induced collagen formation in lung fibroblasts. J Biol Chem. 1989 Oct 15; 264(29):16988-91.
    View in: PubMed
  40. Goldstein RH, Poliks CF, Pilch PF, Smith BD, Fine A. Stimulation of collagen formation by insulin and insulin-like growth factor I in cultures of human lung fibroblasts. Endocrinology. 1989 Feb; 124(2):964-70.
    View in: PubMed
  41. Smith BD, Baldwin CT. Undifferentiated F9 embryonal carcinoma cells produce a short-chain collagen molecule. Biochem J. 1988 Oct 1; 255(1):85-9.
    View in: PubMed
  42. Lee ST, Smith BD, Greenspan DS. Construction of a full-length cDNA encoding human pro-alpha 2(I) collagen and its expression in pro-alpha 2(I)-deficient W8 rat cells. J Biol Chem. 1988 Sep 15; 263(26):13414-8.
    View in: PubMed
  43. Smith BD, Marsilio E. Methylation of the alpha 2(I) collagen gene in chemically transformed rat liver epithelial cells. Biochem J. 1988 Jul 1; 253(1):269-73.
    View in: PubMed
  44. Nakasu S, Fujisawa H, Minagawa T. Purification of characterization of gene 8 product of bacteriophage T3. Virology. 1985 Jun; 143(2):422-34.
    View in: PubMed
  45. Cronlund AL, Smith BD, Kagan HM. Binding of lysyl oxidase to fibrils of type I collagen. Connect Tissue Res. 1985; 14(2):109-19.
    View in: PubMed
  46. Form DM, VanDeWater L, Dvorak HF, Smith BD. Pathogenesis of tumor desmoplasia. II. Collagens synthesized by line 1 and line 10 guinea pig carcinoma cells and by syngeneic fibroblasts in vitro. J Natl Cancer Inst. 1984 Nov; 73(5):1207-14.
    View in: PubMed
  47. Dvorak HF, Form DM, Manseau EJ, Smith BD. Pathogenesis of desmoplasia. I. Immunofluorescence identification and localization of some structural proteins of line 1 and line 10 guinea pig tumors and of healing wounds. J Natl Cancer Inst. 1984 Nov; 73(5):1195-205.
    View in: PubMed
  48. Marsilio E, Sobel ME, Smith BD. Absence of procollagen alpha 2(I) mRNA in chemically transformed rat liver epithelial cells. J Biol Chem. 1984 Feb 10; 259(3):1401-4.
    View in: PubMed
  49. Smith BD, Mahoney AP, Feldman RS. Inverse correlation of collagen production to anchorage independence and tumorigenicity in W8- and M-cell lines. Cancer Res. 1983 Sep; 43(9):4275-82.
    View in: PubMed
  50. Senger DR, Asch BB, Smith BD, Perruzzi CA, Dvorak HF. A secreted phosphoprotein marker for neoplastic transformation of both epithelial and fibroblastic cells. Nature. 1983 Apr 21; 302(5910):714-5.
    View in: PubMed
  51. Yue BY, Baum JL, Smith BD. Identification of collagens synthesized by cultures of normal human corneal and keratoconus stromal cells. Biochim Biophys Acta. 1983 Feb 22; 755(3):318-25.
    View in: PubMed
  52. Smith BD, Silbert CK. Fibronectin and collagen of cultured skin fibroblasts in diabetes mellitus. Biochem Biophys Res Commun. 1981 May 15; 100(1):275-82.
    View in: PubMed
  53. Beldekas JC, Smith B, Gerstenfeld LC, Sonenshein GE, Franzblau C. Effects of 17 beta-estradiol on the biosynthesis of collagen in cultured bovine aortic smooth muscle cells. Biochemistry. 1981 Apr 14; 20(8):2162-7.
    View in: PubMed
  54. Smith BD, Niles R. Characterization of collagen synthesized by normal and chemically transformed rat liver epithelial cell lines. Biochemistry. 1980 Apr 29; 19(9):1820-5.
    View in: PubMed
  55. Smith BD, Biles D, Gonnerman W, Faris B, Levine A, Capparell N, Moolten F, Franzblau C. Collagen synthesis in normal BHK cells and temperature-sensitive chemically transformed BHK cells. In Vitro. 1979 Jun; 15(6):455-62.
    View in: PubMed
  56. Yue BY, Baum JL, Smith BD. Collagen synthesis by cultures of stromal cells from normal human and keratoconus corneas. Biochem Biophys Res Commun. 1979 Feb 14; 86(3):465-72.
    View in: PubMed
  57. Moro L, Smith BD. Identification of collagen alpha1(I) trimer and normal type I collagen in a polyoma virus-induced mouse tumor. Arch Biochem Biophys. 1977 Jul; 182(1):33-41.
    View in: PubMed
  58. Smith BD, McKenney KH, Lustberg TJ. Characterization of collagen precursors found in rat skin and rat bone. Biochemistry. 1977 Jun 28; 16(13):2980-5.
    View in: PubMed
  59. Lichtenstein JR, Byers PH, Smith BD, Martin GR. Identification of the collagenous proteins synthesized by cultured cells from human skin. Biochemistry. 1975 Apr 22; 14(8):1589-94.
    View in: PubMed
  60. Smith BD, Martin GR, Miller EJ, Dorfman A, Swarm R. Nature of the collagen synthesized by a transplanted chondrosarcoma. Arch Biochem Biophys. 1975 Jan; 166(1):181-6.
    View in: PubMed
  61. Martin GR, Byers PH, Smith BD . On the nature of polypeptide precursors of collagen. In: Biology of the Fibroblast. Kulonen, E. and Pikkarainen, J. (eds.). Academic Press. New York. 1973; 339-342.
  62. Smith BD, Byers PH, Martin GR. Production of procollagen by human fibroblasts in culture. Proc Natl Acad Sci U S A. 1972 Nov; 69(11):3260-2.
    View in: PubMed
  63. Lent RW, Smith B, Salcedo LL, Faris B, Franzblau C. Studies on the reduction of elastin. II. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. Biochemistry. 1969 Jul; 8(7):2837-45.
    View in: PubMed
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