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Gene Review

Smad5  -  SMAD family member 5

Mus musculus

Synonyms: 1110051M15Rik, AI451355, Dwarfin-C, Dwf-C, MAD homolog 5, ...
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Disease relevance of Smad5

  • The Smad5 IRES was 4-8-fold more active than the poliovirus IRES in C2C12 cells, which have osteoblastic differentiation ability, but was 5-10-fold less active than the poliovirus IRES in 293T cells [1].
  • Our analysis shows that BMP4/Madh5-dependent signaling, regulated by hypoxia, initiates the differentiation and expansion of erythroid progenitors in the spleen [2].

High impact information on Smad5

  • RUNX2 functions synergistically with Smad1 and Smad5 to regulate bone-specific genes when BMP induces osteogenesis [3].
  • Smad5 is dispensable for adult murine hematopoiesis [4].
  • Here, we evaluate the role of Smad5 in the regulation of hematopoietic stem cell (HSC) fate decisions in adult mice by using an inducible MxCre-mediated conditional knockout model [4].
  • Furthermore, phenotypic characterization of the stem cell compartment revealed normal numbers of primitive lin(-)Sca-1(+)c-Kit(+) (LSK) cells in Smad5(-)(/)(-) BM [4].
  • BMP4 and Madh5 regulate the erythroid response to acute anemia [2].

Biological context of Smad5


Anatomical context of Smad5

  • Its receptor Alk3 and the R-Smad Smad5 are specifically expressed both in proliferating primordial germ cells and in postnatal spermatogonia [9].
  • Here we show that the signaling mediators Smad1-Smad5 are expressed at all stages of mammary gland development [10].
  • On the other hand, Smad1 and Smad5 decreased myogenin-CAT activity but did not induce ALP activity in MyoD-transfected NIH3T3 fibroblasts [11].
  • Previous research has shown that Smad1 is important in the formation of the allantois, while Smad5 has been shown to be critical in the process of angiogenesis [12].
  • We show that defects in amnion and allantois can already be detected at embryonic day (E) 7.5 in Smad5 mutant mice [8].

Other interactions of Smad5

  • Core-binding factor alpha 1 (Cbfa1) induces osteoblastic differentiation of C2C12 cells without interactions with Smad1 and Smad5 [13].
  • The function of NRAGE is independent of Smad signaling, but the introduction of a dominant-negative Smad5 also rescues neural progenitor apoptosis, suggesting that both canonical and noncanonical pathways can converge and regulate BMP-mediated apoptosis [14].
  • Our previous studies have shown that SMAD5, an important intracellular mediator of transforming growth factor beta (TGF-beta) family, is required for normal development of the cardiovascular system in vivo [15].
  • These results suggest that the Smad5-mediated TGF-beta signals may protect cardiomyocytes from apoptosis by maintaining the integrity of the mitochondria, probably through suppression of p53 mediated pathways [15].
  • Smad5 is thought to relay signals of the bone morphogenetic protein pathway [1].

Analytical, diagnostic and therapeutic context of Smad5


  1. Internal ribosome entry site-mediated translation of Smad5 in vivo: requirement for a nuclear event. Shiroki, K., Ohsawa, C., Sugi, N., Wakiyama, M., Miura, K., Watanabe, M., Suzuki, Y., Sugano, S. Nucleic Acids Res. (2002) [Pubmed]
  2. BMP4 and Madh5 regulate the erythroid response to acute anemia. Lenox, L.E., Perry, J.M., Paulson, R.F. Blood (2005) [Pubmed]
  3. RUNX transcription factors as key targets of TGF-beta superfamily signaling. Ito, Y., Miyazono, K. Curr. Opin. Genet. Dev. (2003) [Pubmed]
  4. Smad5 is dispensable for adult murine hematopoiesis. Singbrant, S., Moody, J.L., Blank, U., Karlsson, G., Umans, L., Zwijsen, A., Karlsson, S. Blood (2006) [Pubmed]
  5. Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Yang, X., Castilla, L.H., Xu, X., Li, C., Gotay, J., Weinstein, M., Liu, P.P., Deng, C.X. Development (1999) [Pubmed]
  6. Overexpression of Smurf1 negatively regulates mouse embryonic lung branching morphogenesis by specifically reducing Smad1 and Smad5 proteins. Shi, W., Chen, H., Sun, J., Chen, C., Zhao, J., Wang, Y.L., Anderson, K.D., Warburton, D. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  7. Bone morphogenetic proteins and their antagonists in skin and hair follicle biology. Botchkarev, V.A. J. Invest. Dermatol. (2003) [Pubmed]
  8. Smad5 determines murine amnion fate through the control of bone morphogenetic protein expression and signalling levels. Bosman, E.A., Lawson, K.A., Debruyn, J., Beek, L., Francis, A., Schoonjans, L., Huylebroeck, D., Zwijsen, A. Development (2006) [Pubmed]
  9. Developmental expression of BMP4/ALK3/SMAD5 signaling pathway in the mouse testis: a potential role of BMP4 in spermatogonia differentiation. Pellegrini, M., Grimaldi, P., Rossi, P., Geremia, R., Dolci, S. J. Cell. Sci. (2003) [Pubmed]
  10. Smad3 in the mammary epithelium has a nonredundant role in the induction of apoptosis, but not in the regulation of proliferation or differentiation by transforming growth factor-beta. Yang, Y.A., Tang, B., Robinson, G., Hennighausen, L., Brodie, S.G., Deng, C.X., Wakefield, L.M. Cell Growth Differ. (2002) [Pubmed]
  11. Smad1 and smad5 act downstream of intracellular signalings of BMP-2 that inhibits myogenic differentiation and induces osteoblast differentiation in C2C12 myoblasts. Yamamoto, N., Akiyama, S., Katagiri, T., Namiki, M., Kurokawa, T., Suda, T. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  12. Smad1 and Smad8 function similarly in mammalian central nervous system development. Hester, M., Thompson, J.C., Mills, J., Liu, Y., El-Hodiri, H.M., Weinstein, M. Mol. Cell. Biol. (2005) [Pubmed]
  13. Core-binding factor alpha 1 (Cbfa1) induces osteoblastic differentiation of C2C12 cells without interactions with Smad1 and Smad5. Nishimura, R., Hata, K., Harris, S.E., Ikeda, F., Yoneda, T. Bone (2002) [Pubmed]
  14. NRAGE mediates p38 activation and neural progenitor apoptosis via the bone morphogenetic protein signaling cascade. Kendall, S.E., Battelli, C., Irwin, S., Mitchell, J.G., Glackin, C.A., Verdi, J.M. Mol. Cell. Biol. (2005) [Pubmed]
  15. Disruption of Smad5 gene induces mitochondria-dependent apoptosis in cardiomyocytes. Sun, Y., Zhou, J., Liao, X., Lü, Y., Deng, C., Huang, P., Chen, Q., Yang, X. Exp. Cell Res. (2005) [Pubmed]
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