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Gene Review

Smad3  -  SMAD family member 3

Rattus norvegicus

Synonyms: MAD homolog 3, Mad3, Madh3, Mothers against DPP homolog 3, Mothers against decapentaplegic homolog 3, ...
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Disease relevance of Smad3


High impact information on Smad3

  • We report here the cloning and functional studies of a novel mammalian Mad molecule, Mad3, as well as a rat Mad1 homologue [5].
  • These results suggest that TGF-beta 1 induces apoptosis through the cleavage of BAD in a Smad3-dependent mechanism [6].
  • Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells [6].
  • Subpopulations of Smad2/Smad3-positive and apoptotic nuclei colocalized, indicating a role for Smads in apoptosis [1].
  • The levels of Smad3 and, in particular, Smad4 were enhanced in the normal ventral prostate, as well as in the tumors after castration [7].

Chemical compound and disease context of Smad3


Biological context of Smad3

  • Our results thus demonstrate a novel mechanism of Smad3 function in regulating thyroid cell differentiation by functionally antagonizing the action of the paired domain transcription factor Pax8 [10].
  • In contrast, HGF treatment reduced TGF-beta-dependent activation of p15INK4B promoter, in which Smad3 phosphorylation at the C-terminal region was involved [11].
  • Down-regulation of Smad2 protein by small interfering RNA duplexes affects only basal transcription of FSH(beta), whereas decreased expression of Smad3 abrogates activin-mediated stimulation of FSH(beta) transcription [12].
  • We propose that Smad3 plays an important role in osteoblastic bone formation and might help to elucidate the transcriptional mechanism of bone formation and possibly lead to the development of bone-forming drugs [13].
  • We investigated whether these structural features contribute to differential FSH(beta) transactivation by Smad2 and Smad3 [12].

Anatomical context of Smad3


Associations of Smad3 with chemical compounds

  • The functional interaction between the paired domain transcription factor Pax8 and Smad3 is involved in transforming growth factor-beta repression of the sodium/iodide symporter gene [10].
  • A type I collagen synthesis inhibitor L-azetidine-2-carboxylic acid, as well as osteocalcin (OCN), significantly antagonized Smad3-stimulated ALP activity and mineralization of MC3T3-E1 cells [13].
  • Depletion of cellular polyamines by alpha-difluoromethylornithine (DFMO) increased basal levels of Smad3 and Smad4 proteins, induced their nuclear translocation, and stimulated Smad sequence-specific DNA-binding activity [17].
  • The decline of Smad3 mRNA was evident at day three of post-bleomycin instillation and the expression of Smad3 continually decreased during the reparative phase of lung injury (days 8 and 12), whereas the expression of Smad2 showed little change after bleomycin administration [2].
  • The protein kinase A antagonist H89 abolished the inhibitory effect of PTX on Smad3/4-dependent CTGF transcription, whereas dibutyryl cAMP and forskolin recapitulated the inhibitory effect [8].

Enzymatic interactions of Smad3

  • The different regulation of inhibitory Smad-7 was detected in irradiated and irradiated plus anti-TGFbeta1 treated animals by semiquantitative RT-PCR and the nucleocytoplasmic shuttling of phosphorylated Smad-3 was shown by isolation of nuclear proteins and Western blot analysis [18].

Regulatory relationships of Smad3

  • In cultured rat granulosa cells from early antral follicles, treatment with GDF-9 stimulated the CAGA-luciferase reporter activity and induced the phosphorylation of Smad3 [19].
  • Cotransfection with a Smad3 expressing plasmid further repressed rTERT transcription and c-myc expression, while cotransfection with the corresponding antisense Smad3 construct had the opposite effect [20].

Other interactions of Smad3


Analytical, diagnostic and therapeutic context of Smad3


  1. Activation of the transforming growth factor beta signaling pathway and induction of cytostasis and apoptosis in mammary carcinomas treated with the anticancer agent perillyl alcohol. Ariazi, E.A., Satomi, Y., Ellis, M.J., Haag, J.D., Shi, W., Sattler, C.A., Gould, M.N. Cancer Res. (1999) [Pubmed]
  2. Regulation of Smad3 expression in bleomycin-induced pulmonary fibrosis: a negative feedback loop of TGF-beta signaling. Zhao, Y., Geverd, D.A. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  3. Smad2 and Smad3 play different roles in rat hepatic stellate cell function and alpha-smooth muscle actin organization. Uemura, M., Swenson, E.S., Gaça, M.D., Giordano, F.J., Reiss, M., Wells, R.G. Mol. Biol. Cell (2005) [Pubmed]
  4. DeltaEF1 mediates TGF-beta signaling in vascular smooth muscle cell differentiation. Nishimura, G., Manabe, I., Tsushima, K., Fujiu, K., Oishi, Y., Imai, Y., Maemura, K., Miyagishi, M., Higashi, Y., Kondoh, H., Nagai, R. Dev. Cell (2006) [Pubmed]
  5. Regulation of transforming growth factor beta- and activin-induced transcription by mammalian Mad proteins. Chen, Y., Lebrun, J.J., Vale, W. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  6. Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells. Kim, B.C., Mamura, M., Choi, K.S., Calabretta, B., Kim, S.J. Mol. Cell. Biol. (2002) [Pubmed]
  7. Increased smad expression and activation are associated with apoptosis in normal and malignant prostate after castration. Brodin, G., ten Dijke, P., Funa, K., Heldin, C.H., Landström, M. Cancer Res. (1999) [Pubmed]
  8. Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. Lin, S.L., Chen, R.H., Chen, Y.M., Chiang, W.C., Lai, C.F., Wu, K.D., Tsai, T.J. J. Am. Soc. Nephrol. (2005) [Pubmed]
  9. Smad3 specific inhibitor, naringenin, decreases the expression of extracellular matrix induced by TGF-beta1 in cultured rat hepatic stellate cells. Liu, X., Wang, W., Hu, H., Tang, N., Zhang, C., Liang, W., Wang, M. Pharm. Res. (2006) [Pubmed]
  10. The functional interaction between the paired domain transcription factor Pax8 and Smad3 is involved in transforming growth factor-beta repression of the sodium/iodide symporter gene. Costamagna, E., García, B., Santisteban, P. J. Biol. Chem. (2004) [Pubmed]
  11. TGF-beta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions. Mori, S., Matsuzaki, K., Yoshida, K., Furukawa, F., Tahashi, Y., Yamagata, H., Sekimoto, G., Seki, T., Matsui, H., Nishizawa, M., Fujisawa, J., Okazaki, K. Oncogene (2004) [Pubmed]
  12. Smad3 mediates activin-induced transcription of follicle-stimulating hormone beta-subunit gene. Suszko, M.I., Balkin, D.M., Chen, Y., Woodruff, T.K. Mol. Endocrinol. (2005) [Pubmed]
  13. Smad3 promotes alkaline phosphatase activity and mineralization of osteoblastic MC3T3-E1 cells. Sowa, H., Kaji, H., Yamaguchi, T., Sugimoto, T., Chihara, K. J. Bone Miner. Res. (2002) [Pubmed]
  14. Localization of Smads, the TGF-beta family intracellular signaling components during endochondral ossification. Sakou, T., Onishi, T., Yamamoto, T., Nagamine, T., Sampath, T., Ten Dijke, P. J. Bone Miner. Res. (1999) [Pubmed]
  15. Treatment with anti-TGF-beta antibody ameliorates chronic progressive nephritis by inhibiting Smad/TGF-beta signaling. Fukasawa, H., Yamamoto, T., Suzuki, H., Togawa, A., Ohashi, N., Fujigaki, Y., Uchida, C., Aoki, M., Hosono, M., Kitagawa, M., Hishida, A. Kidney Int. (2004) [Pubmed]
  16. Smads 2 and 3 are differentially activated by transforming growth factor-beta (TGF-beta ) in quiescent and activated hepatic stellate cells. Constitutive nuclear localization of Smads in activated cells is TGF-beta-independent. Liu, C., Gaça, M.D., Swenson, E.S., Vellucci, V.F., Reiss, M., Wells, R.G. J. Biol. Chem. (2003) [Pubmed]
  17. Activation of TGF-beta-Smad signaling pathway following polyamine depletion in intestinal epithelial cells. Liu, L., Santora, R., Rao, J.N., Guo, X., Zou, T., Zhang, H.M., Turner, D.J., Wang, J.Y. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  18. Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1)-treatment in irradiated rat tissue. Schultze-Mosgau, S., Blaese, M.A., Grabenbauer, G., Wehrhan, F., Kopp, J., Amann, K., Rodemann, H.P., Rödel, F. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. (2004) [Pubmed]
  19. Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5. Mazerbourg, S., Klein, C., Roh, J., Kaivo-Oja, N., Mottershead, D.G., Korchynskyi, O., Ritvos, O., Hsueh, A.J. Mol. Endocrinol. (2004) [Pubmed]
  20. Role of Smad3 in the regulation of rat telomerase reverse transcriptase by TGFbeta. Hu, B., Tack, D.C., Liu, T., Wu, Z., Ullenbruch, M.R., Phan, S.H. Oncogene (2006) [Pubmed]
  21. Transforming growth factor-beta1 inhibition of vascular smooth muscle cell activation is mediated via Smad3. Feinberg, M.W., Watanabe, M., Lebedeva, M.A., Depina, A.S., Hanai, J., Mammoto, T., Frederick, J.P., Wang, X.F., Sukhatme, V.P., Jain, M.K. J. Biol. Chem. (2004) [Pubmed]
  22. Effects of Chinese traditional compound, JinSanE, on expression of TGF-beta1 and TGF-beta1 type II receptor mRNA, Smad3 and Smad7 on experimental hepatic fibrosis in vivo. Song, S.L., Gong, Z.J., Zhang, Q.R., Huang, T.X. World J. Gastroenterol. (2005) [Pubmed]
  23. JinSanE Decoction, A Chinese Herbal Medicine, Inhibits Expression of TGF-beta1/Smads in Experimental Hepatic Fibrosis in Rats. Song, S.L., Gong, Z.J., Huang, Y.Q., Zhang, Q.R., Huang, T.X. Am. J. Chin. Med. (2006) [Pubmed]
  24. Constitutive phosphorylation and nuclear localization of Smad3 are correlated with increased collagen gene transcription in activated hepatic stellate cells. Inagaki, Y., Mamura, M., Kanamaru, Y., Greenwel, P., Nemoto, T., Takehara, K., Ten Dijke, P., Nakao, A. J. Cell. Physiol. (2001) [Pubmed]
  25. Pioglitazone limits cyclosporine nephrotoxicity in rats. Pereira, M.G., C??mara, N.O., Campaholle, G., Cenedeze, M.A., de Paula Antunes Teixeira, V., Dos Reis, M.A., Pacheco-Silva, A. Int. Immunopharmacol. (2006) [Pubmed]
  26. Effects of transforming growth factor-beta1 and signal protein Smad3 on rat cardiomyocyte hypertrophy. Huang, J., Qin, G.H., Hu, C.X., Gong, L.Y., Cheng, F.Z., Ma, Y.X., Lu, Z.Y. Chin. Med. J. (2004) [Pubmed]
  27. Nitric oxide induces TIMP-1 expression by activating the transforming growth factor beta-Smad signaling pathway. Akool, e.l.-.S., Doller, A., Müller, R., Gutwein, P., Xin, C., Huwiler, A., Pfeilschifter, J., Eberhardt, W. J. Biol. Chem. (2005) [Pubmed]
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