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Gene Review

SMAD7  -  SMAD family member 7

Homo sapiens

Synonyms: CRCS3, MAD homolog 7, MAD homolog 8, MADH7, MADH8, ...
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Disease relevance of SMAD7


High impact information on SMAD7

  • Smad7 interacts stably with the activated TGFbeta type I receptor, thereby blocking the association, phosphorylation, and activation of Smad2 [5].
  • Specifically, acetylation of Smad7 protects it against ubiquitination and degradation mediated by the ubiquitin ligase Smurf1 [6].
  • Control of Smad7 stability by competition between acetylation and ubiquitination [6].
  • These studies thus define Smad7 as an adaptor in an E3 ubiquitin-ligase complex that targets the TGF beta receptor for degradation [7].
  • Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7 [7].

Chemical compound and disease context of SMAD7


Biological context of SMAD7

  • A -303 to +672 SMAD7 region contained a palindromic GTCTAGAC Smad binding element (SBE) between nucleotides -179 and -172 that was necessary for the induction of a Smad7 promoter luciferase reporter gene by TGF-beta [12].
  • To define the molecular mechanisms of negative control of TGF-beta signaling, we have isolated the human SMAD7 gene and characterized its promoter region [12].
  • Some epithelia were transfected with an expression plasmid encoding SMAD7 to block TGF-beta-SMAD signaling [13].
  • Unexpectedly, we found some gene duplications; SMAD7 appears to be more frequently amplified (10%) than the three other genes (4-7%) [1].
  • Moreover, the HRs associated with one additional copy of SMAD7 were 1.76, p = 0.00024 [OS] and 1.64, p = 0.00048 [DFS] respectively, showing a graded effect of SMAD7 on patient outcome depending on gene copy number that suggests a dose-and-effect basis [14].

Anatomical context of SMAD7


Associations of SMAD7 with chemical compounds

  • Correspondingly, Smad7 bound poorly to a mutant ALK-4 bearing serine to alanine substitutions in four putative phosphorylation sites in its GS domain [19].
  • Finally, N-acetylcysteine, TGF-beta antibody, Smad7, and dominant-negative Smad3 reversed beta-HB (1 mmol/L)-induced growth inhibition at 48 hours [20].
  • The regulating role of Smad signaling in high glucose-induced collagen synthesis was determined by inducing overexpression of the inhibitory Smad7 in a stable Smad7-expressing tubular cell line [21].
  • CONCLUSION: The data show that SB-202190 and SB-203580 suppress TGFbeta-dependent activation of genes that are important for the acquisition of invasive behavior, while having no effect on the expression of the natural TGFbeta inhibitor Smad7 [22].
  • METHODS: Alpha-smooth muscle actin (alpha-SMA), Smad2/3, and Smad7 protein were assessed by Western blot [23].

Physical interactions of SMAD7

  • Deletion of the AP-1 binding site in the Smad7 promoter completely abolished UV stimulation of SMAD7 transcription [24].
  • In this report, we show that TGF-beta can stabilize Smad7 mRNA and activate Smad7 transcription [25].
  • We demonstrate that on TGF-beta treatment, endogenous SMAD complex can bind to a Smad7 promoter DNA as short as 14 or 16 bp that contains the 8-bp SBE in gel mobility shift and supershift assays [25].
  • Ski along with Smad4 binds and represses the smad7 promoter, whereas the repression mechanism by SnoN is not clear [26].
  • SnoN co-repressor binds and represses smad7 gene promoter [26].
  • The SRF binding domain of Smad7 mapped to the C-terminal half of the Smad7 molecule [27].

Co-localisations of SMAD7

  • Smad4 co-localized with Smad7 and Smurf1 primarily in the cytoplasm and in peripheral cell protrusions [28].

Regulatory relationships of SMAD7

  • Furthermore, TGF-beta1-induced apoptosis was prevented by inhibition of Smad7 expression, by antisense mRNA in stably transfected cell lines or upon transient transfection with antisense oligonucleotides in several investigated cell lines [17].
  • Activation of endogenous NF-kappaB by tumour necrosis factor-alpha (TNF-alpha) was also able to inhibit the Smad7 promoter in human embryonic kidney 293 cells [29].
  • This Smad7 inhibition is enhanced by co-expression of Smurf1 [30].
  • Further, Smad7 expression inhibited alpha1 (I) collagen and alpha-smooth muscle actin expression [15].
  • These results suggest that the myostatin signal transduction pathway is regulated by Smad7 through a negative feedback mechanism [30].
  • Our findings suggest that Smad7 inhibits TGF-beta signaling in the nucleus by a novel mechanism [31].

Other interactions of SMAD7


Analytical, diagnostic and therapeutic context of SMAD7

  • In contrast to SMAD2 deletion, for which no clinical relevance was observed, hazard ratios (HR) in a multivariate analysis associated with SMAD7 deletion [overall survival (OS): HR = 0.43, p = 0.0012; disease-free survival (DFS): HR = 0.50, p = 0.0033] indicated a favorable outcome for these patients [14].
  • Inhibitory SMAD7 mRNA was significantly higher in lesional skin as compared to unaffected skin, and significantly decreased after UVA1 phototherapy [2].
  • We now report that Smad7 mRNA levels are increased in human pancreatic cancer by comparison with the normal pancreas, and that by in situ hybridization, Smad7 is over-expressed in the cancer cells within the tumor mass [34].
  • Collectively, these data show that the Tregs that mediate col(V)-induced tolerance to lung allografts do not express SMAD7 and, therefore, are permissive to TGF-beta-mediated signaling [35].
  • Immunofluorescence analysis revealed that the inhibitory Smad, Smad7, was exported to the cytoplasm from the nucleus by the treatment with Ac-SDKP [36].


  1. Combined copy status of 18q21 genes in colorectal cancer shows frequent retention of SMAD7. Boulay, J.L., Mild, G., Reuter, J., Lagrange, M., Terracciano, L., Lowy, A., Laffer, U., Orth, B., Metzger, U., Stamm, B., Martinoli, S., Herrmann, R., Rochlitz, C. Genes Chromosomes Cancer (2001) [Pubmed]
  2. Ultraviolet A1 phototherapy decreases inhibitory SMAD7 gene expression in localized scleroderma. Kreuter, A., Hyun, J., Skrygan, M., Sommer, A., Tomi, N.S., Breuckmann, F., Altmeyer, P., Gambichler, T. Arch. Dermatol. Res. (2006) [Pubmed]
  3. Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring. Yu, H., Bock, O., Bayat, A., Ferguson, M.W., Mrowietz, U. Journal of plastic, reconstructive & aesthetic surgery : JPRAS. (2006) [Pubmed]
  4. Smad7 abrogates transforming growth factor-beta1-mediated growth inhibition in COLO-357 cells through functional inactivation of the retinoblastoma protein. Boyer Arnold, N., Korc, M. J. Biol. Chem. (2005) [Pubmed]
  5. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y.Y., Grinnell, B.W., Richardson, M.A., Topper, J.N., Gimbrone, M.A., Wrana, J.L., Falb, D. Cell (1997) [Pubmed]
  6. Control of Smad7 stability by competition between acetylation and ubiquitination. Grönroos, E., Hellman, U., Heldin, C.H., Ericsson, J. Mol. Cell (2002) [Pubmed]
  7. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Kavsak, P., Rasmussen, R.K., Causing, C.G., Bonni, S., Zhu, H., Thomsen, G.H., Wrana, J.L. Mol. Cell (2000) [Pubmed]
  8. 2-Methoxyestradiol-induced apoptosis in prostate cancer cells requires Smad7. Davoodpour, P., Landström, M. J. Biol. Chem. (2005) [Pubmed]
  9. Transforming growth factor-beta and Smad signalling in kidney diseases. Wang, W., Koka, V., Lan, H.Y. Nephrology (Carlton, Vic.) (2005) [Pubmed]
  10. Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. Nakao, A., Fujii, M., Matsumura, R., Kumano, K., Saito, Y., Miyazono, K., Iwamoto, I. J. Clin. Invest. (1999) [Pubmed]
  11. Effects of perindopril and valsartan on expression of transforming growth factor-beta-Smads in experimental hepatic fibrosis in rats. Xu, W., Song, S., Huang, Y., Gong, Z. J. Gastroenterol. Hepatol. (2006) [Pubmed]
  12. Smad3 and Smad4 mediate transcriptional activation of the human Smad7 promoter by transforming growth factor beta. von Gersdorff, G., Susztak, K., Rezvani, F., Bitzer, M., Liang, D., Böttinger, E.P. J. Biol. Chem. (2000) [Pubmed]
  13. TGF-beta Suppresses IFN-{gamma}-STAT1-Dependent Gene Transcription by Enhancing STAT1-PIAS1 Interactions in Epithelia but Not Monocytes/Macrophages. Reardon, C., McKay, D.M. J. Immunol. (2007) [Pubmed]
  14. SMAD7 is a prognostic marker in patients with colorectal cancer. Boulay, J.L., Mild, G., Lowy, A., Reuter, J., Lagrange, M., Terracciano, L., Laffer, U., Herrmann, R., Rochlitz, C. Int. J. Cancer (2003) [Pubmed]
  15. Abrogation of transforming growth factor-beta signaling by SMAD7 inhibits collagen gel contraction of human dermal fibroblasts. Kopp, J., Preis, E., Said, H., Hafemann, B., Wickert, L., Gressner, A.M., Pallua, N., Dooley, S. J. Biol. Chem. (2005) [Pubmed]
  16. Modulation of proliferation-specific and differentiation-specific markers in human keratinocytes by SMAD7. Smith, L., Dahler, A.L., Cavanagh, L.L., Popa, C., Barnes, L.M., Serewko-Auret, M.M., Fai Wong, C., Saunders, N.A. Exp. Cell Res. (2004) [Pubmed]
  17. Smad7 mediates apoptosis induced by transforming growth factor beta in prostatic carcinoma cells. Landström, M., Heldin, N.E., Bu, S., Hermansson, A., Itoh, S., ten Dijke, P., Heldin, C.H. Curr. Biol. (2000) [Pubmed]
  18. Inhibition of the transforming growth factor-beta/Smad signaling pathway in the epithelium of oral lichen. Karatsaidis, A., Schreurs, O., Axéll, T., Helgeland, K., Schenck, K. J. Invest. Dermatol. (2003) [Pubmed]
  19. Phosphorylation regulation of the interaction between Smad7 and activin type I receptor. Liu, X., Nagarajan, R.P., Vale, W., Chen, Y. FEBS Lett. (2002) [Pubmed]
  20. Beta-hydroxybutyrate-induced growth inhibition and collagen production in HK-2 cells are dependent on TGF-beta and Smad3. Guh, J.Y., Chuang, T.D., Chen, H.C., Hung, W.C., Lai, Y.H., Shin, S.J., Chuang, L.Y. Kidney Int. (2003) [Pubmed]
  21. Role of TGF-beta signaling in extracellular matrix production under high glucose conditions. Li, J.H., Huang, X.R., Zhu, H.J., Johnson, R., Lan, H.Y. Kidney Int. (2003) [Pubmed]
  22. Interfering with TGFbeta-induced Smad3 nuclear accumulation differentially affects TGFbeta-dependent gene expression. Lindemann, R.K., Nordheim, A., Dittmer, J. Mol. Cancer (2003) [Pubmed]
  23. Effect of IFN-gamma and dexamethasone on TGF-beta1-induced human fetal lung fibroblast-myofibroblast differentiation. Gu, L., Zhu, Y.J., Guo, Z.J., Xu, X.X., Xu, W.B. Acta Pharmacol. Sin. (2004) [Pubmed]
  24. Ultraviolet irradiation induces Smad7 via induction of transcription factor AP-1 in human skin fibroblasts. Quan, T., He, T., Voorhees, J.J., Fisher, G.J. J. Biol. Chem. (2005) [Pubmed]
  25. Transforming growth factor beta -inducible independent binding of SMAD to the Smad7 promoter. Denissova, N.G., Pouponnot, C., Long, J., He, D., Liu, F. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  26. SnoN co-repressor binds and represses smad7 gene promoter. Briones-Orta, M.A., Sosa-Garrocho, M., Moreno-Alvarez, P., Fonseca-Sánchez, M.A., Macías-Silva, M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  27. Inhibition of transforming growth factor beta-enhanced serum response factor-dependent transcription by SMAD7. Camoretti-Mercado, B., Fernandes, D.J., Dewundara, S., Churchill, J., Ma, L., Kogut, P.C., McConville, J.F., Parmacek, M.S., Solway, J. J. Biol. Chem. (2006) [Pubmed]
  28. Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. Morén, A., Imamura, T., Miyazono, K., Heldin, C.H., Moustakas, A. J. Biol. Chem. (2005) [Pubmed]
  29. Repression of transforming-growth-factor-beta-mediated transcription by nuclear factor kappaB. Nagarajan, R.P., Chen, F., Li, W., Vig, E., Harrington, M.A., Nakshatri, H., Chen, Y. Biochem. J. (2000) [Pubmed]
  30. Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory Smad7 by a negative feedback mechanism. Zhu, X., Topouzis, S., Liang, L.F., Stotish, R.L. Cytokine (2004) [Pubmed]
  31. Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation. Zhang, S., Fei, T., Zhang, L., Zhang, R., Chen, F., Ning, Y., Han, Y., Feng, X.H., Meng, A., Chen, Y.G. Mol. Cell. Biol. (2007) [Pubmed]
  32. STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling. Datta, P.K., Moses, H.L. Mol. Cell. Biol. (2000) [Pubmed]
  33. Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Mori, Y., Chen, S.J., Varga, J. Arthritis Rheum. (2003) [Pubmed]
  34. The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Kleeff, J., Ishiwata, T., Maruyama, H., Friess, H., Truong, P., Büchler, M.W., Falb, D., Korc, M. Oncogene (1999) [Pubmed]
  35. Differential expression of Smad7 transcripts identifies the CD4+CD45RChigh regulatory T cells that mediate type V collagen-induced tolerance to lung allografts. Mizobuchi, T., Yasufuku, K., Zheng, Y., Haque, M.A., Heidler, K.M., Woods, K., Smith, G.N., Cummings, O.W., Fujisawa, T., Blum, J.S., Wilkes, D.S. J. Immunol. (2003) [Pubmed]
  36. N-Acetyl-seryl-aspartyl-lysyl-proline inhibits TGF-beta-mediated plasminogen activator inhibitor-1 expression via inhibition of Smad pathway in human mesangial cells. Kanasaki, K., Koya, D., Sugimoto, T., Isono, M., Kashiwagi, A., Haneda, M. J. Am. Soc. Nephrol. (2003) [Pubmed]
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