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Gene Review

Smad1  -  SMAD family member 1

Mus musculus

Synonyms: AI528653, Dwarfin-A, Dwf-A, MAD homolog 1, Mad-related protein 1, ...
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Disease relevance of Smad1


High impact information on Smad1

  • Smad proteins activated by TGF-beta form a complex with FoxO proteins to turn on the growth inhibitory gene p21Cip1 [4].
  • Smad proteins transmit TGFbeta signals from the cell surface to the nucleus [6].
  • Most ligands of the family signal through transmembrane serine/threonine kinase receptors and SMAD proteins to regulate cellular functions [7].
  • These results underscore the need to tightly balance BMP and MAPK signaling pathways through Smad1 [8].
  • Smad1(C/C) mutants recapitulate many Smad1(-/-) phenotypes, including defective allantois formation and the lack of primordial germ cells (PGC), but also show phenotypes that are both more severe (head and branchial arches) and less severe (allantois growth) than the null [8].

Chemical compound and disease context of Smad1


Biological context of Smad1


Anatomical context of Smad1


Associations of Smad1 with chemical compounds

  • SB202190, a p38 mitogen-activated protein kinase inhibitor, inhibited this effect of BMP-7; however, since SB202190 suppressed phosphorylation of Smad1/5, this may be due to blockade of BMP receptor activation [20].
  • The biological effects of type I serine/threonine kinase receptors and Smad proteins were examined using an adenovirus-based vector system [21].
  • Low-level bisphenol A increases production of glial fibrillary acidic protein in differentiating astrocyte progenitor cells through excessive STAT3 and Smad1 activation [22].
  • We have studied the effects of two new synthetic triterpenoids, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivative, 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im), on transforming growth factor (TGF)-beta/Smad signaling [23].
  • Together these data provide the first evidence that activation of BMP receptor serine/threonine kinase stimulates the PI 3 kinase/Akt pathway and define a role for this signal transduction pathway in BMP-specific Smad function during osteoblast differentiation [24].

Physical interactions of Smad1

  • SMAD 8 binding to mice Msx1 basal promoter is required for transcriptional activation [25].
  • 2. Furthermore, the recruitment of an HDAC/Sin3A complex to Nkx3.2 requires that Nkx3.2 interact with Smad1 and -4 [26].
  • Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells [27].
  • In this study we tested the hypothesis that a putative Smad-binding region containing the sequence AGACTGTCTGGAC is involved in the activation of the OPN promoter by members of the TGFbeta superfamily [28].
  • For instance, in fetal brain, it has been shown that the neurogenic transcription factor Neurogenin1 inhibits formation of a STAT3/p300/ Smad1 complex and that the oligodendrocytic transcription factor OLIG2 does the same [29].

Enzymatic interactions of Smad1

  • We also found that BMP4-induced differentiation of PGCs from epiblast in vitro was fully dependent on the existence of phosphorylated SMAD1 [30].
  • Endogenous Smad pathway was activated in the obstructed kidney after UUO in wild-type mice as judged by the increase of phosphorylated Smad2 or phosphorylated Smad2/3-positive cells in renal interstitial area [31].
  • TGF-beta signaling is transduced from the cell membrane to the nucleus by means of specific type I and type II receptors and phosphorylated Smad proteins [32].

Co-localisations of Smad1


Regulatory relationships of Smad1

  • Smurf1 has been found to interact with BMP-activated Smad1 and -5 and to mediate degradation of these Smad proteins [34].
  • However, Smad does not directly induce Runx2 expression; an additional step of de novo protein synthesis is required [35].
  • BMP-induced Smad1 and Smad5 activation of GCCG-mediated transcription was blocked in the presence of CIZ overexpression [36].
  • BMP-4 triggered the phosphorylation of Smad1, suggesting that the effect of BMP-4 on FSH secretion is due to the activation of the BMPs signaling pathway [37].
  • Transcripts of Smad1 through -5 were constantly expressed in the epidermis regardless of changes in TGFbeta signaling, state of differentiation and stages of carcinogenesis [2].

Other interactions of Smad1

  • p38MAPK acts in the BMP7-dependent stimulatory pathway during epithelial cell morphogenesis and is regulated by Smad1 [16].
  • This increase is probably due to the activation of the gene encoding 204 (Ifi204) by Smad transcription factor, including Smad1, -4, and -5 [38].
  • Here we report that Smad-induced junB functions as an upstream activator of Runx2 expression [35].
  • During skin carcinogenesis, loss of Smad1 through -5 and overexpression of Smad7 may contribute to the loss of growth inhibition mediated by TGFbeta superfamily members, thus resulting in tumor progression [2].
  • The bone morphogenetic protein 2 signaling mediator Smad1 participates predominantly in osteogenic and not in chondrogenic differentiation in mesenchymal progenitors C3H10T1/2 [39].
  • Taken together, miR-199a(*) is the first BMP2 responsive microRNA found to adversely regulate early chondrocyte differentiation via direct targeting of the Smad1 transcription factor [40].

Analytical, diagnostic and therapeutic context of Smad1


  1. Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia. Horiki, M., Imamura, T., Okamoto, M., Hayashi, M., Murai, J., Myoui, A., Ochi, T., Miyazono, K., Yoshikawa, H., Tsumaki, N. J. Cell Biol. (2004) [Pubmed]
  2. Smads mediate signaling of the TGFbeta superfamily in normal keratinocytes but are lost during skin chemical carcinogenesis. He, W., Cao, T., Smith, D.A., Myers, T.E., Wang, X.J. Oncogene (2001) [Pubmed]
  3. Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction. Chuva de Sousa Lopes, S.M., Feijen, A., Korving, J., Korchynskyi, O., Larsson, J., Karlsson, S., ten Dijke, P., Lyons, K.M., Goldschmeding, R., Doevendans, P., Mummery, C.L. Dev. Dyn. (2004) [Pubmed]
  4. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Seoane, J., Le, H.V., Shen, L., Anderson, S.A., Massagué, J. Cell (2004) [Pubmed]
  5. The hepatitis B virus encoded oncoprotein pX amplifies TGF-beta family signaling through direct interaction with Smad4: potential mechanism of hepatitis B virus-induced liver fibrosis. Lee, D.K., Park, S.H., Yi, Y., Choi, S.G., Lee, C., Parks, W.T., Cho, H., de Caestecker, M.P., Shaul, Y., Roberts, A.B., Kim, S.J. Genes Dev. (2001) [Pubmed]
  6. Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Waldrip, W.R., Bikoff, E.K., Hoodless, P.A., Wrana, J.L., Robertson, E.J. Cell (1998) [Pubmed]
  7. Genetic analysis of the mammalian transforming growth factor-beta superfamily. Chang, H., Brown, C.W., Matzuk, M.M. Endocr. Rev. (2002) [Pubmed]
  8. In vivo convergence of BMP and MAPK signaling pathways: impact of differential Smad1 phosphorylation on development and homeostasis. Aubin, J., Davy, A., Soriano, P. Genes Dev. (2004) [Pubmed]
  9. Transforming growth factor-beta 1 inhibits non-pathogenic Gram negative bacteria-induced NF-kappa B recruitment to the interleukin-6 gene promoter in intestinal epithelial cells through modulation of histone acetylation. Haller, D., Holt, L., Kim, S.C., Schwabe, R.F., Sartor, R.B., Jobin, C. J. Biol. Chem. (2003) [Pubmed]
  10. 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]
  11. Effects of candesartan, an angiotensin II type 1 receptor blocker, on diabetic nephropathy in KK/Ta mice. Liao, J., Kobayashi, M., Kanamuru, Y., Nakamura, S., Makita, Y., Funabiki, K., Horikoshi, S., Tomino, Y. J. Nephrol. (2003) [Pubmed]
  12. Cell type-specific intervention of transforming growth factor beta/Smad signaling suppresses collagen gene expression and hepatic fibrosis in mice. Inagaki, Y., Kushida, M., Higashi, K., Itoh, J., Higashiyama, R., Hong, Y.Y., Kawada, N., Namikawa, K., Kiyama, H., Bou-Gharios, G., Watanabe, T., Okazaki, I., Ikeda, K. Gastroenterology (2005) [Pubmed]
  13. BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells. Rajan, P., Panchision, D.M., Newell, L.F., McKay, R.D. J. Cell Biol. (2003) [Pubmed]
  14. 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]
  15. The cardiac determination factor, Nkx2-5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer. Brown, C.O., Chi, X., Garcia-Gras, E., Shirai, M., Feng, X.H., Schwartz, R.J. J. Biol. Chem. (2004) [Pubmed]
  16. p38MAPK acts in the BMP7-dependent stimulatory pathway during epithelial cell morphogenesis and is regulated by Smad1. Hu, M.C., Wasserman, D., Hartwig, S., Rosenblum, N.D. J. Biol. Chem. (2004) [Pubmed]
  17. E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. Zhao, M., Qiao, M., Oyajobi, B.O., Mundy, G.R., Chen, D. J. Biol. Chem. (2003) [Pubmed]
  18. Inactivation of menin, the product of the multiple endocrine neoplasia type 1 gene, inhibits the commitment of multipotential mesenchymal stem cells into the osteoblast lineage. Sowa, H., Kaji, H., Canaff, L., Hendy, G.N., Tsukamoto, T., Yamaguchi, T., Miyazono, K., Sugimoto, T., Chihara, K. J. Biol. Chem. (2003) [Pubmed]
  19. Spatio-temporal activation of Smad1 and Smad5 in vivo: monitoring transcriptional activity of Smad proteins. Monteiro, R.M., de Sousa Lopes, S.M., Korchynskyi, O., ten Dijke, P., Mummery, C.L. J. Cell. Sci. (2004) [Pubmed]
  20. Bone morphogenetic protein signaling in articular chondrocyte differentiation. Nishihara, A., Fujii, M., Sampath, T.K., Miyazono, K., Reddi, A.H. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  21. Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Fujii, M., Takeda, K., Imamura, T., Aoki, H., Sampath, T.K., Enomoto, S., Kawabata, M., Kato, M., Ichijo, H., Miyazono, K. Mol. Biol. Cell (1999) [Pubmed]
  22. Low-level bisphenol A increases production of glial fibrillary acidic protein in differentiating astrocyte progenitor cells through excessive STAT3 and Smad1 activation. Yamaguchi, H., Zhu, J., Yu, T., Sasaki, K., Umetsu, H., Kidachi, Y., Ryoyama, K. Toxicology (2006) [Pubmed]
  23. Synthetic triterpenoids enhance transforming growth factor beta/Smad signaling. Suh, N., Roberts, A.B., Birkey Reffey, S., Miyazono, K., Itoh, S., ten Dijke, P., Heiss, E.H., Place, A.E., Risingsong, R., Williams, C.R., Honda, T., Gribble, G.W., Sporn, M.B. Cancer Res. (2003) [Pubmed]
  24. Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription. Ghosh-Choudhury, N., Abboud, S.L., Nishimura, R., Celeste, A., Mahimainathan, L., Choudhury, G.G. J. Biol. Chem. (2002) [Pubmed]
  25. SMAD 8 binding to mice Msx1 basal promoter is required for transcriptional activation. Binato, R., Alvarez Martinez, C.E., Pizzatti, L., Robert, B., Abdelhay, E. Biochem. J. (2006) [Pubmed]
  26. Smad-dependent recruitment of a histone deacetylase/Sin3A complex modulates the bone morphogenetic protein-dependent transcriptional repressor activity of Nkx3.2. Kim, D.W., Lassar, A.B. Mol. Cell. Biol. (2003) [Pubmed]
  27. Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells. Suzuki, A., Raya, A., Kawakami, Y., Morita, M., Matsui, T., Nakashima, K., Gage, F.H., Rodríguez-Esteban, C., Izpisúa Belmonte, J.C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  28. TGFbeta and BMP-2 activation of the OPN promoter: roles of smad- and hox-binding elements. Hullinger, T.G., Pan, Q., Viswanathan, H.L., Somerman, M.J. Exp. Cell Res. (2001) [Pubmed]
  29. Cell fate determination regulated by a transcriptional signal network in the developing mouse brain. Fukuda, S., Taga, T. Anatomical science international / Japanese Association of Anatomists. (2005) [Pubmed]
  30. SMAD1 signaling is critical for initial commitment of germ cell lineage from mouse epiblast. Hayashi, K., Kobayashi, T., Umino, T., Goitsuka, R., Matsui, Y., Kitamura, D. Mech. Dev. (2002) [Pubmed]
  31. Smad3 deficiency attenuates renal fibrosis, inflammation,and apoptosis after unilateral ureteral obstruction. Inazaki, K., Kanamaru, Y., Kojima, Y., Sueyoshi, N., Okumura, K., Kaneko, K., Yamashiro, Y., Ogawa, H., Nakao, A. Kidney Int. (2004) [Pubmed]
  32. Receptor-regulated and inhibitory Smads are critical in regulating transforming growth factor beta-mediated Meckel's cartilage development. Ito, Y., Bringas, P., Mogharei, A., Zhao, J., Deng, C., Chai, Y. Dev. Dyn. (2002) [Pubmed]
  33. Impaired spermatogenesis and male fertility defects in CIZ/Nmp4-disrupted mice. Nakamoto, T., Shiratsuchi, A., Oda, H., Inoue, K., Matsumura, T., Ichikawa, M., Saito, T., Seo, S., Maki, K., Asai, T., Suzuki, T., Hangaishi, A., Yamagata, T., Aizawa, S., Noda, M., Nakanishi, Y., Hirai, H. Genes Cells (2004) [Pubmed]
  34. Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo. Zhao, M., Qiao, M., Harris, S.E., Oyajobi, B.O., Mundy, G.R., Chen, D. J. Biol. Chem. (2004) [Pubmed]
  35. Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein. Lee, K.S., Hong, S.H., Bae, S.C. Oncogene (2002) [Pubmed]
  36. Negative regulation of bone morphogenetic protein/Smad signaling by Cas-interacting zinc finger protein in osteoblasts. Shen, Z.J., Nakamoto, T., Tsuji, K., Nifuji, A., Miyazono, K., Komori, T., Hirai, H., Noda, M. J. Biol. Chem. (2002) [Pubmed]
  37. BMP-4 inhibits follicle-stimulating hormone secretion in ewe pituitary. Faure, M.O., Nicol, L., Fabre, S., Fontaine, J., Mohoric, N., McNeilly, A., Taragnat, C. J. Endocrinol. (2005) [Pubmed]
  38. The interferon-inducible p204 protein acts as a transcriptional coactivator of Cbfa1 and enhances osteoblast differentiation. Liu, C.J., Chang, E., Yu, J., Carlson, C.S., Prazak, L., Yu, X.P., Ding, B., Lengyel, P., Di Cesare, P.E. J. Biol. Chem. (2005) [Pubmed]
  39. The bone morphogenetic protein 2 signaling mediator Smad1 participates predominantly in osteogenic and not in chondrogenic differentiation in mesenchymal progenitors C3H10T1/2. Ju, W., Hoffmann, A., Verschueren, K., Tylzanowski, P., Kaps, C., Gross, G., Huylebroeck, D. J. Bone Miner. Res. (2000) [Pubmed]
  40. miR-199a, a bone morphogenic protein 2-responsive MicroRNA, regulates chondrogenesis via direct targeting to Smad1. Lin, E.A., Kong, L., Bai, X.H., Luan, Y., Liu, C.J. J. Biol. Chem. (2009) [Pubmed]
  41. Enamel matrix derivative stimulates core binding factor alpha1/Runt-related transcription factor-2 expression via activation of Smad1 in C2C12 cells. Takayama, T., Suzuki, N., Narukawa, M., Tokunaga, T., Otsuka, K., Ito, K. J. Periodontol. (2005) [Pubmed]
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