The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

Smad3  -  SMAD family member 3

Mus musculus

Synonyms: AU022421, MAD homolog 3, Mad3, Madh3, Mothers against DPP homolog 3, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of Smad3


High impact information on Smad3

  • Moreover, introducing a human Smad3 cDNA into the mouse Smad2 locus similarly rescues anterior-posterior patterning and definitive endoderm formation and results in adult viability [4].
  • Finally, we show that removal of one copy of Smad3 in the context of a Smad2-deficient epiblast results in a failure to specify all axial midline tissues [5].
  • TGF-beta inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3 [6].
  • Indeed, activated NK cells from Smad3(-/-) mice produce more IFN-gamma in vivo than NK cells from wild-type mice [7].
  • Together the data demonstrate that the Smad3 pathway is central to the pathogenesis of interstitial fibrosis and suggest that inhibitors of this pathway may have clinical application in the treatment of obstructive nephropathy [8].

Chemical compound and disease context of Smad3


Biological context of Smad3

  • Our results indicate that endogenous TGF-beta signaling regulates the rate of adipogenesis, and that Smad2 and Smad3 have distinct functions in this endogenous control of differentiation [15].
  • Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model [2].
  • A prominent pathway of transforming growth factor (TGF)-beta signaling involves receptor-dependent phosphorylation of Smad2 and Smad3, which then translocate to the nucleus to activate transcription of target genes [16].
  • Loss of Smad3 modulates wound healing [17].
  • In vitro glutathione S-transferase pulldown competition experiments revealed the SHP-mediated repression of Smad3 transactivation through competition with its co-activator p300 [18].

Anatomical context of Smad3

  • Basal level and TGF-beta-inducible expression of Smad7 are selectively decreased, whereas Smad3 expression is increased both in scleroderma skin and in explanted scleroderma fibroblasts in culture [19].
  • However, Smad2 and not Smad3 mRNA is expressed in the visceral endoderm, potentially explaining why the primary defect in Smad2 mutant embryos originates in this cell population [20].
  • Hypoxia inhibition of adipocytogenesis in human bone marrow stromal cells requires transforming growth factor-beta/Smad3 signaling [21].
  • Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation [22].
  • Interactions of Smad3 with GABP (when coexpressed or endogenous to B cells) were shown by coprecipitation and by mammalian two-hybrid assay [23].

Associations of Smad3 with chemical compounds

  • PD98059 and curcumin enhanced Smad3-induced ALP activity and mineralization, whereas SB203580 inhibited them [24].
  • In addition, Smad3 activation was stimulated by IGF-I and blocked by LY294002, suggesting cross-talk between Smad and the phosphatidylinositol-3 kinase/AKT pathways [25].
  • Furthermore, terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining after UUO showed significantly reduced number of tubular apoptotic cells in the obstructed kidney of Smad3(-/-) mice when compared with that of Smad3(+/+) mice [9].
  • Pretreatment with PTH or overexpression of Smad3 decreased the number of apoptotic cells induced by dexamethasone and etoposide [26].
  • Moreover, sphingosine 1-phosphate fails to induce chemotaxis or inhibit the growth of Smad3-deficient keratinocytes, suggesting that Smad3 plays an unexpected functional role as a new target in sphingosine 1-phosphate signaling [27].

Physical interactions of Smad3

  • Time course luciferase assays and time course gel mobility shift assays reveal that the Smad3/4 complex is largely responsible for the immediate response of the SM22alpha promoter to TGF-beta induction, and also contributes to the maximal promoter activity [28].
  • A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A [29].
  • This TGF-beta1/Smad3 action involves an inhibitory effect on AP-1 activity and DNA binding that results in an inhibition of the AP-1-driven induction of the PPARbeta/delta promoter [30].
  • CONCLUSION: Smad 3 binds all three known isoforms of Dishevelled and binds Dishevelled 1 in vivo [31].

Enzymatic interactions of Smad3

  • Nuclear detection of Smad3 and phosphorylated Smads within intraluminal fibroblasts coincided with increased intraluminal deposition of fibronectin and collagen [32].

Regulatory relationships of Smad3

  • VEGF secretion in response to TGF-beta1 is enhanced by hypoxia and by overexpression of Smad3/4 and hypoxia-inducible factor-1alpha/beta (HIF-1alpha/beta) [33].
  • Myocardin enhances Smad3-mediated transforming growth factor-beta1 signaling in a CArG box-independent manner: Smad-binding element is an important cis element for SM22alpha transcription in vivo [34].
  • Essential role of Smad3 in the inhibition of inflammation-induced PPARbeta/delta expression [30].
  • Collectively, these data suggest that activins use both SMAD2- and SMAD3-dependent mechanisms to stimulate FSHbeta transcription in mouse gonadotrope cells [35].
  • Also similar to the GLalpha promoter, overexpression of p300 enhances Smad3/4-mediated promoter activity, whereas E1A represses promoter activity [36].

Other interactions of Smad3

  • Moreover, Smad2 or Smad3 with Smad4 enhanced the proteolytic pathway of p57(Kip2) [37].
  • Loss of Smad3 only partially blocked the effects of TGF-beta1 on differentiation [38].
  • COL1A2 promoter activity was dose dependently induced by TGF-beta1, which was further augmented by adenoviral overexpression of Smad3, but was downregulated by Smad7 [39].
  • Together, these results reveal a model for how TGF-beta, through Smad3-mediated transcriptional repression, inhibits myogenic differentiation [6].
  • Overexpression of Runx3 in mice increased germ-line alpha (GLalpha) transcription, and transcription was further augmented when B lymphoma and LPS-activated murine spleen cells were co-transfected with Smad3/4 [40].

Analytical, diagnostic and therapeutic context of Smad3


  1. Smad3 mutant mice develop metastatic colorectal cancer. Zhu, Y., Richardson, J.A., Parada, L.F., Graff, J.M. Cell (1998) [Pubmed]
  2. Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model. Vijayachandra, K., Lee, J., Glick, A.B. Cancer Res. (2003) [Pubmed]
  3. Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis. Bonniaud, P., Kolb, M., Galt, T., Robertson, J., Robbins, C., Stampfli, M., Lavery, C., Margetts, P.J., Roberts, A.B., Gauldie, J. J. Immunol. (2004) [Pubmed]
  4. Mice exclusively expressing the short isoform of Smad2 develop normally and are viable and fertile. Dunn, N.R., Koonce, C.H., Anderson, D.C., Islam, A., Bikoff, E.K., Robertson, E.J. Genes Dev. (2005) [Pubmed]
  5. Cell fate decisions within the mouse organizer are governed by graded Nodal signals. Vincent, S.D., Dunn, N.R., Hayashi, S., Norris, D.P., Robertson, E.J. Genes Dev. (2003) [Pubmed]
  6. TGF-beta inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3. Liu, D., Black, B.L., Derynck, R. Genes Dev. (2001) [Pubmed]
  7. Pro- and antiinflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Yu, J., Wei, M., Becknell, B., Trotta, R., Liu, S., Boyd, Z., Jaung, M.S., Blaser, B.W., Sun, J., Benson, D.M., Mao, H., Yokohama, A., Bhatt, D., Shen, L., Davuluri, R., Weinstein, M., Marcucci, G., Caligiuri, M.A. Immunity (2006) [Pubmed]
  8. Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. Sato, M., Muragaki, Y., Saika, S., Roberts, A.B., Ooshima, A. J. Clin. Invest. (2003) [Pubmed]
  9. Smad3 deficiency attenuates renal fibrosis, inflammation,and apoptosis after unilateral ureteral obstruction. Inazaki, K., Kanamaru, Y., Kojima, Y., Sueyoshi, N., Okumura, K., Kaneko, K., Yamashiro, Y., Ogawa, H., Nakao, A. Kidney Int. (2004) [Pubmed]
  10. Essential role of Smad3 in angiotensin II-induced vascular fibrosis. Wang, W., Huang, X.R., Canlas, E., Oka, K., Truong, L.D., Deng, C., Bhowmick, N.A., Ju, W., Bottinger, E.P., Lan, H.Y. Circ. Res. (2006) [Pubmed]
  11. Targeted disruption of TGF-beta/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma. Lakos, G., Takagawa, S., Chen, S.J., Ferreira, A.M., Han, G., Masuda, K., Wang, X.J., DiPietro, L.A., Varga, J. Am. J. Pathol. (2004) [Pubmed]
  12. Reduction of Smad3 accelerates re-epithelialization in a murine model of colitis. Tokumasa, A., Katsuno, T., Tanaga, T.S., Yokote, K., Saito, Y., Suzuki, Y. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  13. Smad3 as a mediator of the fibrotic response. Flanders, K.C. International journal of experimental pathology. (2004) [Pubmed]
  14. SMAD3 regulates gonadal tumorigenesis. Li, Q., Graff, J.M., O'Connor, A.E., Loveland, K.L., Matzuk, M.M. Mol. Endocrinol. (2007) [Pubmed]
  15. Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation. Choy, L., Skillington, J., Derynck, R. J. Cell Biol. (2000) [Pubmed]
  16. Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts. Piek, E., Ju, W.J., Heyer, J., Escalante-Alcalde, D., Stewart, C.L., Weinstein, M., Deng, C., Kucherlapati, R., Bottinger, E.P., Roberts, A.B. J. Biol. Chem. (2001) [Pubmed]
  17. Loss of Smad3 modulates wound healing. Ashcroft, G.S., Roberts, A.B. Cytokine Growth Factor Rev. (2000) [Pubmed]
  18. Orphan Nuclear Receptor Small Heterodimer Partner Inhibits Transforming Growth Factor-beta Signaling by Repressing SMAD3 Transactivation. Suh, J.H., Huang, J., Park, Y.Y., Seong, H.A., Kim, D., Shong, M., Ha, H., Lee, I.K., Lee, K., Wang, L., Choi, H.S. J. Biol. Chem. (2006) [Pubmed]
  19. Deficient Smad7 expression: a putative molecular defect in scleroderma. Dong, C., Zhu, S., Wang, T., Yoon, W., Li, Z., Alvarez, R.J., ten Dijke, P., White, B., Wigley, F.M., Goldschmidt-Clermont, P.J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  20. Formation of the definitive endoderm in mouse is a Smad2-dependent process. Tremblay, K.D., Hoodless, P.A., Bikoff, E.K., Robertson, E.J. Development (2000) [Pubmed]
  21. Hypoxia inhibition of adipocytogenesis in human bone marrow stromal cells requires transforming growth factor-beta/Smad3 signaling. Zhou, S., Lechpammer, S., Greenberger, J.S., Glowacki, J. J. Biol. Chem. (2005) [Pubmed]
  22. Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation. Li, T.F., Darowish, M., Zuscik, M.J., Chen, D., Schwarz, E.M., Rosier, R.N., Drissi, H., O'Keefe, R.J. J. Bone Miner. Res. (2006) [Pubmed]
  23. Transforming growth factor beta enhances the glucocorticoid response of the mouse mammary tumor virus promoter through Smad and GA-binding proteins. Aurrekoetxea-Hernández, K., Buetti, E. J. Virol. (2004) [Pubmed]
  24. Activations of ERK1/2 and JNK by transforming growth factor beta negatively regulate Smad3-induced alkaline phosphatase activity and mineralization in mouse osteoblastic cells. Sowa, H., Kaji, H., Yamaguchi, T., Sugimoto, T., Chihara, K. J. Biol. Chem. (2002) [Pubmed]
  25. Smoking Induces Glomerulosclerosis in Aging Estrogen-Deficient Mice through Cross-Talk between TGF-beta1 and IGF-I Signaling Pathways. Elliot, S.J., Karl, M., Berho, M., Xia, X., Pereria-Simon, S., Espinosa-Heidmann, D., Striker, G.E. J. Am. Soc. Nephrol. (2006) [Pubmed]
  26. Parathyroid hormone-Smad3 axis exerts anti-apoptotic action and augments anabolic action of transforming growth factor beta in osteoblasts. Sowa, H., Kaji, H., Iu, M.F., Tsukamoto, T., Sugimoto, T., Chihara, K. J. Biol. Chem. (2003) [Pubmed]
  27. Involvement of Smad signaling in sphingosine 1-phosphate-mediated biological responses of keratinocytes. Sauer, B., Vogler, R., von Wenckstern, H., Fujii, M., Anzano, M.B., Glick, A.B., Schäfer-Korting, M., Roberts, A.B., Kleuser, B. J. Biol. Chem. (2004) [Pubmed]
  28. Smad proteins regulate transcriptional induction of the SM22alpha gene by TGF-beta. Chen, S., Kulik, M., Lechleider, R.J. Nucleic Acids Res. (2003) [Pubmed]
  29. A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A. Zhang, L., Duan, C.J., Binkley, C., Li, G., Uhler, M.D., Logsdon, C.D., Simeone, D.M. Mol. Cell. Biol. (2004) [Pubmed]
  30. Essential role of Smad3 in the inhibition of inflammation-induced PPARbeta/delta expression. Tan, N.S., Michalik, L., Di-Poï, N., Ng, C.Y., Mermod, N., Roberts, A.B., Desvergne, B., Wahli, W. EMBO J. (2004) [Pubmed]
  31. Interaction between Smad 3 and Dishevelled in murine embryonic craniofacial mesenchymal cells. Warner, D.R., Greene, R.M., Pisano, M.M. Orthodontics & craniofacial research. (2005) [Pubmed]
  32. Smad3 deficiency ameliorates experimental obliterative bronchiolitis in a heterotopic tracheal transplantation model. Ramirez, A.M., Takagawa, S., Sekosan, M., Jaffe, H.A., Varga, J., Roman, J. Am. J. Pathol. (2004) [Pubmed]
  33. Mechanisms underlying TGF-{beta}1-induced expression of VEGF and Flk-1 in mouse macrophages and their implications for angiogenesis. Jeon, S.H., Chae, B.C., Kim, H.A., Seo, G.Y., Seo, D.W., Chun, G.T., Kim, N.S., Yie, S.W., Byeon, W.H., Eom, S.H., Ha, K.S., Kim, Y.M., Kim, P.H. J. Leukoc. Biol. (2007) [Pubmed]
  34. Myocardin enhances Smad3-mediated transforming growth factor-beta1 signaling in a CArG box-independent manner: Smad-binding element is an important cis element for SM22alpha transcription in vivo. Qiu, P., Ritchie, R.P., Fu, Z., Cao, D., Cumming, J., Miano, J.M., Wang, D.Z., Li, H.J., Li, L. Circ. Res. (2005) [Pubmed]
  35. Both SMAD2 and SMAD3 mediate activin-stimulated expression of the follicle-stimulating hormone beta subunit in mouse gonadotrope cells. Bernard, D.J. Mol. Endocrinol. (2004) [Pubmed]
  36. Analysis of transforming growth factor-beta1-induced Ig germ-line gamma2b transcription and its implication for IgA isotype switching. Park, S.R., Seo, G.Y., Choi, A.J., Stavnezer, J., Kim, P.H. Eur. J. Immunol. (2005) [Pubmed]
  37. Smad-mediated transcription is required for transforming growth factor-beta 1-induced p57(Kip2) proteolysis in osteoblastic cells. Nishimori, S., Tanaka, Y., Chiba, T., Fujii, M., Imamura, T., Miyazono, K., Ogasawara, T., Kawaguchi, H., Igarashi, T., Fujita, T., Tanaka, K., Toyoshima, H. J. Biol. Chem. (2001) [Pubmed]
  38. Unique and redundant roles of Smad3 in TGF-beta-mediated regulation of long bone development in organ culture. Alvarez, J., Serra, R. Dev. Dyn. (2004) [Pubmed]
  39. BMP-7 opposes TGF-beta1-mediated collagen induction in mouse pulmonary myofibroblasts through Id2. Izumi, N., Mizuguchi, S., Inagaki, Y., Saika, S., Kawada, N., Nakajima, Y., Inoue, K., Suehiro, S., Friedman, S.L., Ikeda, K. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  40. p300 cooperates with Smad3/4 and Runx3 in TGFbeta1-induced IgA isotype expression. Park, S.R., Lee, E.K., Kim, B.C., Kim, P.H. Eur. J. Immunol. (2003) [Pubmed]
  41. Smad3 knock-out mice as a useful model to study intestinal fibrogenesis. Zanninelli, G., Vetuschi, A., Sferra, R., D'Angelo, A., Fratticci, A., Continenza, M.A., Chiaramonte, M., Gaudio, E., Caprilli, R., Latella, G. World J. Gastroenterol. (2006) [Pubmed]
  42. Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. Goumans, M.J., Mummery, C. Int. J. Dev. Biol. (2000) [Pubmed]
  43. Fetal and adult fibroblasts have similar TGF-beta-mediated, Smad-dependent signaling pathways. Colwell, A.S., Krummel, T.M., Longaker, M.T., Lorenz, H.P. Plast. Reconstr. Surg. (2006) [Pubmed]
WikiGenes - Universities