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Gene Review

Smad7  -  SMAD family member 7

Mus musculus

Synonyms: MAD homolog 7, MAD homolog 8, Madh7, Madh8, Mothers against DPP homolog 7, ...
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Disease relevance of Smad7

  • Our results suggest that the reduction of Smad7 protein resulting from enhanced ubiquitin-dependent degradation plays a pathogenic role in progression of tubulointerstitial fibrosis [1].
  • C57BL/6 mice with bleomycin-induced lungs received an intratracheal injection of a recombinant adenovirus carrying mice Smad7 cDNA [2].
  • This may represent a new approach to the control of IBD, particularly during active phases when its Smad7 profile resembles that of hapten-induced colitis [3].
  • Background & Aims: Defective transforming growth factor (TGF)-beta1 signaling due to high levels of Smad7 is a feature of inflammatory bowel disease (IBD) [3].
  • Further, constitutive expression of exogenous Smad7 potently enhanced skeletal muscle differentiation and cellular hypertrophy [4].

High impact information on Smad7

  • The antagonism is mediated through up-regulation of Smad7 synthesis and induction of stable associations between ligand-activated TGF-beta receptors and inhibitory Smad7 [5].
  • To address this issue, we developed transgenic mice expressing Smad7, an intracellular antagonist of TGF-beta/Smad signaling, selectively in mature T cells using a plasmid construct coding a promoter element (the distal lck promoter) that directs high expression in peripheral T cells [6].
  • To determine the functions of Smad7, we have expressed Smad7 in transgenic mice, utilizing a keratin K5 promoter (K5.Smad7) [7].
  • Our study provides evidence that Smad7 is a potent in vivo inhibitor for signal transduction of the TGFbeta superfamily during development and maintenance of homeostasis of multiple epithelial tissues [7].
  • Compared with sham-operated kidneys, the level of Smad7 protein, but not mRNA, decreased progressively in UUO kidneys, whereas immunoreactivity for nuclear phosphorylated Smad2 and Smad3 and renal fibrosis were inversely increased [1].

Biological context of Smad7


Anatomical context of Smad7

  • The inhibitory effect of Smad7 on adipocyte differentiation and its cooperation with TGF-beta was associated with the C-domain of Smad7 [12].
  • Although acceleration of healing of the burned cornea was also observed in mice lacking Smad3, the effects on epithelial and stromal healing were less pronounced than those in corneas treated with Smad7 [13].
  • Despite apparent activation of the intracellular transforming growth factor-beta signaling pathway in the lesional dermis, the expression of transforming growth factor-beta-inducible Smad7 was not upregulated [14].
  • In contrast, Smad6 was selectively expressed at high levels, e.g. in intramembranous bone whereas Smad7 was prominent in seminiferous tubules of the testis, demonstrating distinct expression of these genes in non-cardiovascular tissues [15].
  • Immunohistochemistry evaluation showed a significant increase of CD3+ T cell, TGF-beta1 and Smad7 staining in the small and large intestine mucosa of Smad3 null mice as compared to wild-type mice [16].

Associations of Smad7 with chemical compounds


Physical interactions of Smad7

  • Finally, we document that Smad7 directly interacts with MyoD and enhances MyoD transcriptional activity [4].

Regulatory relationships of Smad7


Other interactions of Smad7


Analytical, diagnostic and therapeutic context of Smad7

  • Smad3 and -4 were found in nuclei of normal corneal epithelium, whereas they were absent in nuclei of migrating cells in association with Smad7 upregulation on epithelial debridement [31].
  • Oral administration of Smad7 antisense oligonucleotide to colitic mice restored TGF-beta1 signaling via Smad3 and ameliorated inflammation in hapten-induced colitis [3].
  • We also demonstrate by transient transgenesis that overexpression of Smad7 in mouse zygotes inhibits development beyond the 2-cell stage [32].
  • Lens epithelial cells in the Cre adv control group exhibited a fibroblastic appearance at days 5 and 10 and the capsular break was sealed with fibrous tissue, while Smad7 adv-treated cells around the capsular break retained their epithelial morphology and the break was not sealed [33].
  • CONCLUSIONS: Smad7 gene transfer modulates injury-induced wound healing of conjunctival tissue in mice, suggesting that this strategy may be effective in preventing excessive scarring following filtration surgery [34].


  1. Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice. Fukasawa, H., Yamamoto, T., Togawa, A., Ohashi, N., Fujigaki, Y., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Suzuki, S., Kitagawa, M., Hishida, A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  2. 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]
  3. Inhibition of Smad7 With a Specific Antisense Oligonucleotide Facilitates TGF-beta1-Mediated Suppression of Colitis. Boirivant, M., Pallone, F., Di Giacinto, C., Fina, D., Monteleone, I., Marinaro, M., Caruso, R., Colantoni, A., Palmieri, G., Sanchez, M., Strober, W., Macdonald, T.T., Monteleone, G. Gastroenterology (2006) [Pubmed]
  4. Smad7 promotes and enhances skeletal muscle differentiation. Kollias, H.D., Perry, R.L., Miyake, T., Aziz, A., McDermott, J.C. Mol. Cell. Biol. (2006) [Pubmed]
  5. A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA. Bitzer, M., von Gersdorff, G., Liang, D., Dominguez-Rosales, A., Beg, A.A., Rojkind, M., Böttinger, E.P. Genes Dev. (2000) [Pubmed]
  6. Blockade of transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. Nakao, A., Miike, S., Hatano, M., Okumura, K., Tokuhisa, T., Ra, C., Iwamoto, I. J. Exp. Med. (2000) [Pubmed]
  7. Overexpression of Smad7 results in severe pathological alterations in multiple epithelial tissues. He, W., Li, A.G., Wang, D., Han, S., Zheng, B., Goumans, M.J., Ten Dijke, P., Wang, X.J. EMBO J. (2002) [Pubmed]
  8. Antagonistic effects of Smad2 versus Smad7 are sensitive to their expression level during tooth development. Ito, Y., Zhao, J., Mogharei, A., Shuler, C.F., Weinstein, M., Deng, C., Chai, Y. J. Biol. Chem. (2001) [Pubmed]
  9. Regulation of Smad7 promoter by direct association with Smad3 and Smad4. Nagarajan, R.P., Zhang, J., Li, W., Chen, Y. J. Biol. Chem. (1999) [Pubmed]
  10. Smad protein mediated transforming growth factor beta1 induction of apoptosis in the MDPC-23 odontoblast-like cell line. He, W.X., Niu, Z.Y., Zhao, S.L., Smith, A.J. Arch. Oral Biol. (2005) [Pubmed]
  11. Amifostine does not prevent activation of TGFbeta1 but induces smad 7 activation in megakaryocytes irradiated in vivo. Segreto, H.R., Ferreira, A.T., Kimura, E.T., Franco, M., Egami, M.I., Silva, M.R., Segreto, R.A. Am. J. Hematol. (2002) [Pubmed]
  12. Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation. Choy, L., Skillington, J., Derynck, R. J. Cell Biol. (2000) [Pubmed]
  13. Expression of Smad7 in mouse eyes accelerates healing of corneal tissue after exposure to alkali. Saika, S., Ikeda, K., Yamanaka, O., Miyamoto, T., Ohnishi, Y., Sato, M., Muragaki, Y., Ooshima, A., Nakajima, Y., Kao, W.W., Flanders, K.C., Roberts, A.B. Am. J. Pathol. (2005) [Pubmed]
  14. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma. Takagawa, S., Lakos, G., Mori, Y., Yamamoto, T., Nishioka, K., Varga, J. J. Invest. Dermatol. (2003) [Pubmed]
  15. Developmentally regulated expression of Smad3, Smad4, Smad6, and Smad7 involved in TGF-beta signaling. Luukko, K., Ylikorkala, A., Mäkelä, T.P. Mech. Dev. (2001) [Pubmed]
  16. 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]
  17. 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]
  18. Phosphorylation of Smad7 at Ser-249 does not interfere with its inhibitory role in transforming growth factor-beta-dependent signaling but affects Smad7-dependent transcriptional activation. Pulaski, L., Landström, M., Heldin, C.H., Souchelnytskyi, S. J. Biol. Chem. (2001) [Pubmed]
  19. Inhibitory effect of genistein on mouse colon cancer MC-26 cells involved TGF-beta1/Smad pathway. Yu, Z., Tang, Y., Hu, D., Li, J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  20. alpha3beta1 integrin-controlled Smad7 regulates reepithelialization during wound healing in mice. Reynolds, L.E., Conti, F.J., Silva, R., Robinson, S.D., Iyer, V., Rudling, R., Cross, B., Nye, E., Hart, I.R., Dipersio, C.M., Hodivala-Dilke, K.M. J. Clin. Invest. (2008) [Pubmed]
  21. Type I transforming growth factor beta receptor binds to and activates phosphatidylinositol 3-kinase. Yi, J.Y., Shin, I., Arteaga, C.L. J. Biol. Chem. (2005) [Pubmed]
  22. Growth/differentiation factor-5 induces growth arrest and apoptosis in mouse B lineage cells with modulation by Smad. Nakahara, T., Tominaga, K., Koseki, T., Yamamoto, M., Yamato, K., Fukuda, J., Nishihara, T. Cell. Signal. (2003) [Pubmed]
  23. Smad7 Inhibits chondrocyte differentiation at multiple steps during endochondral bone formation and down-regulates p38 MAPK pathways. Iwai, T., Murai, J., Yoshikawa, H., Tsumaki, N. J. Biol. Chem. (2008) [Pubmed]
  24. 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]
  25. Efficient TGF-beta induction of the Smad7 gene requires cooperation between AP-1, Sp1, and Smad proteins on the mouse Smad7 promoter. Brodin, G., Ahgren, A., ten Dijke, P., Heldin, C.H., Heuchel, R. J. Biol. Chem. (2000) [Pubmed]
  26. Smad7 and protein phosphatase 1alpha are critical determinants in the duration of TGF-beta/ALK1 signaling in endothelial cells. Valdimarsdottir, G., Goumans, M.J., Itoh, F., Itoh, S., Heldin, C.H., ten Dijke, P. BMC Cell Biol. (2006) [Pubmed]
  27. Cloning of Smad2, Smad3, Smad4, and Smad7 from the goldfish pituitary and evidence for their involvement in activin regulation of goldfish FSHbeta promoter activity. Lau, M.T., Ge, W. Gen. Comp. Endocrinol. (2005) [Pubmed]
  28. 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]
  29. SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation. Kume, S., Haneda, M., Kanasaki, K., Sugimoto, T., Araki, S., Isshiki, K., Isono, M., Uzu, T., Guarente, L., Kashiwagi, A., Koya, D. J. Biol. Chem. (2007) [Pubmed]
  30. Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in mice. Hamzavi, J., Ehnert, S., Godoy, P., Ciuclan, L., Weng, H., Mertens, P.R., Heuchel, R., Dooley, S. J. Cell. Mol. Med. (2008) [Pubmed]
  31. Role of p38 MAP kinase in regulation of cell migration and proliferation in healing corneal epithelium. Saika, S., Okada, Y., Miyamoto, T., Yamanaka, O., Ohnishi, Y., Ooshima, A., Liu, C.Y., Weng, D., Kao, W.W. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  32. Expression of the inhibitory Smad7 in early mouse development and upregulation during embryonic vasculogenesis. Zwijsen, A., van Rooijen, M.A., Goumans, M.J., Dewulf, N., Bosman, E.A., ten Dijke, P., Mummery, C.L., Huylebroeck, D. Dev. Dyn. (2000) [Pubmed]
  33. Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial-mesenchymal transition of lens epithelium in mice. Saika, S., Ikeda, K., Yamanaka, O., Sato, M., Muragaki, Y., Ohnishi, Y., Ooshima, A., Nakajima, Y., Namikawa, K., Kiyama, H., Flanders, K.C., Roberts, A.B. Lab. Invest. (2004) [Pubmed]
  34. Gene transfer of Smad7 modulates injury-induced conjunctival wound healing in mice. Yamanaka, O., Ikeda, K., Saika, S., Miyazaki, K., Ooshima, A., Ohnishi, Y. Mol. Vis. (2006) [Pubmed]
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