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Gene Review

Smad4  -  SMAD family member 4

Rattus norvegicus

Synonyms: MAD homolog 4, Madh4, Mothers against DPP homolog 4, Mothers against decapentaplegic homolog 4, SMAD 4
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Disease relevance of Smad4


High impact information on Smad4


Chemical compound and disease context of Smad4


Biological context of Smad4


Anatomical context of Smad4

  • Also immunohistochemistry revealed that the main site of TGR1, Smad2, Smad4, and Smad7 expression was mainly in hepatocytes of the preneoplastic lesions of a rat liver [9].
  • In this paper, the functional relevance of Smad4, in the control of thyroid differentiation genes and thyroid-specific transcription factors, has been investigated [12].
  • The results of image and statistical analysis showed that generally the expression of Smad1, Smad2 and Smad4 in the testis tended to increase gradually with the growth of the rat [13].
  • The immunolocalization of Smad4 was exclusively at the cytoplasm of Leydig cells and the nuclei were negative throughout the testicular development [13].
  • PPARalpha inhibits TGF-beta-induced beta5 integrin transcription in vascular smooth muscle cells by interacting with Smad4 [14].

Associations of Smad4 with chemical compounds

  • 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 [7].
  • Mutations of Smad2 were detected in 2 out of 12 HCCs (16.7%) induced by the CDAA diet, a GGT-to-GGC transition (Gly to Gly) at codon 30 and a TCT-to-GCT (Ser to Ala) transversion at codon 118, without any TGF-betaRII or Smad4 alterations [11].
  • We demonstrated that Ang II inhibited TGF-beta1-induced nuclear accumulation of Smad3 and Smad4 [15].
  • Losartan administration (8 wk, 15 mg. kg(-1). day(-1)) normalized total Smad 2 overexpression in infarct scar and remnant heart tissue and normalized Smad 4 in infarct scar [16].

Regulatory relationships of Smad4

  • Furthermore, adenoviral-mediated expression of dominant negative Smad4 blocked the ability of TGF-beta to activate acinar cell MAP kinase, demonstrating that this activation is downstream of Smads [17].

Other interactions of Smad4

  • We investigated expressions and localizations of TGR1, Smad2, Smad4, and Smad7 by using semi-quantitative RT-PCR and immunohistochemistry in preneoplastic lesions during rat chemical hepatocarcinogenesis induced by Solt and Farber's method [9].
  • Aortic TGF-beta1-type II receptor (TbetaRII), its downstream molecules p-similar to mad-mother against decapentaplegic (SMAD)2/3 and SMAD4, fibronectin, and collagen also increased with age [18].
  • Brief BMP4 application caused Smad1 translocation from the neuronal cytoplasm into the nucleus, where it is known to regulate transcription in association with Smad4 [19].

Analytical, diagnostic and therapeutic context of Smad4


  1. Smad2 overexpression enhances Smad4 gene expression and suppresses CBFA1 gene expression in osteoblastic osteosarcoma ROS17/2.8 cells and primary rat calvaria cells. Li, J., Tsuji, K., Komori, T., Miyazono, K., Wrana, J.L., Ito, Y., Nifuji, A., Noda, M. J. Biol. Chem. (1998) [Pubmed]
  2. Mutations of the Smad2 and Smad4 genes in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats. Tsujiuchi, T., Sasaki, Y., Tsutsumi, M., Konishi, Y. Mol. Carcinog. (2000) [Pubmed]
  3. SMAD pathway mediation of BDNF and TGF beta 2 regulation of proliferation and differentiation of hippocampal granule neurons. Lu, J., Wu, Y., Sousa, N., Almeida, O.F. Development (2005) [Pubmed]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. Transforming growth factor beta (TGF-beta) signaling is regulated by electrical activity in skeletal muscle cells. TGF-beta type I receptor is transcriptionally regulated by myotube excitability. Ugarte, G., Brandan, E. J. Biol. Chem. (2006) [Pubmed]
  9. Expression and localization of the transforming growth factor-beta type I receptor and Smads in preneoplastic lesions during chemical hepatocarcinogenesis in rats. Park, d.o. .Y., Lee, C.H., Sol, M.Y., Suh, K.S., Yoon, S.Y., Kim, J.W. J. Korean Med. Sci. (2003) [Pubmed]
  10. Expression of Smad2 and Smad4, transforming growth factor-beta signal transducers in rat endometrium during the estrous cycle, pre-, and peri-implantation. Lin, H.Y., Wang, H.M., Li, Q.L., Liu, D.L., Zhang, X., Liu, G.Y., Qian, D., Zhu, C. Anim. Reprod. Sci. (2004) [Pubmed]
  11. Alterations of the transforming growth factor-beta signaling pathway in hepatocellular carcinomas induced endogenously and exogenously in rats. Sasaki, Y., Tsujiuchi, T., Murata, N., Tsutsumi, M., Konishi, Y. Jpn. J. Cancer Res. (2001) [Pubmed]
  12. TGF-beta control of rat thyroid follicular cells differentiation. Nicolussi, A., D'Inzeo, S., Santulli, M., Colletta, G., Coppa, A. Mol. Cell. Endocrinol. (2003) [Pubmed]
  13. Expression and localization of Smad1, Smad2 and Smad4 proteins in rat testis during postnatal development. Hu, J., Zhang, Y.Q., Liu, X.P., Wang, R.A., Jin, Y., Xu, R.J. Asian J. Androl. (2003) [Pubmed]
  14. PPARalpha inhibits TGF-beta-induced beta5 integrin transcription in vascular smooth muscle cells by interacting with Smad4. Kintscher, U., Lyon, C., Wakino, S., Bruemmer, D., Feng, X., Goetze, S., Graf, K., Moustakas, A., Staels, B., Fleck, E., Hsueh, W.A., Law, R.E. Circ. Res. (2002) [Pubmed]
  15. Angiotensin II promotes the proliferation of activated pancreatic stellate cells by Smad7 induction through a protein kinase C pathway. Hama, K., Ohnishi, H., Aoki, H., Kita, H., Yamamoto, H., Osawa, H., Sato, K., Tamada, K., Mashima, H., Yasuda, H., Sugano, K. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  16. Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro. Hao, J., Wang, B., Jones, S.C., Jassal, D.S., Dixon, I.M. Am. J. Physiol. Heart Circ. Physiol. (2000) [Pubmed]
  17. Smad4 mediates activation of mitogen-activated protein kinases by TGF-beta in pancreatic acinar cells. Simeone, D.M., Zhang, L., Graziano, K., Nicke, B., Pham, T., Schaefer, C., Logsdon, C.D. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  18. Matrix metalloproteinase 2 activation of transforming growth factor-beta1 (TGF-beta1) and TGF-beta1-type II receptor signaling within the aged arterial wall. Wang, M., Zhao, D., Spinetti, G., Zhang, J., Jiang, L.Q., Pintus, G., Monticone, R., Lakatta, E.G. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  19. Signaling by bone morphogenetic proteins and Smad1 modulates the postnatal differentiation of cerebellar cells. Angley, C., Kumar, M., Dinsio, K.J., Hall, A.K., Siegel, R.E. J. Neurosci. (2003) [Pubmed]
  20. 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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