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Gene Review

Smad4  -  SMAD family member 4

Mus musculus

Synonyms: AW743858, D18Wsu70e, DPC4, Deletion target in pancreatic carcinoma 4 homolog, Dpc4, ...
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Disease relevance of Smad4

  • Taking advantage of this fact, we constructed previously a cis-compound Apc(delta716) Smad4 mutant, the intestinal polyps of which progress to very invasive adenocarcinomas [1].
  • In both simple Apc(Delta716) and compound Apc(Delta716) Smad4 mutants, MVD increased in a polyp size-dependent manner only in the polyps expanded beyond a threshold of about 1 mm in diameter [2].
  • Thus, the phenotypes of breast tumors in vivo paralleled that of human breast cancer cell lines in terms of Smad2P and Smad4 expression [3].
  • Loss of Smad4 was inversely correlated with the presence of axillary lymph node metastases [3].
  • We recently inactivated its mouse homologue Smad4 and demonstrated its role in the malignant progression of benign adenomas to invasive adenocarcinomas by analyzing mice with Apc and Smad4 compound mutations [4].

High impact information on Smad4


Biological context of Smad4


Anatomical context of Smad4

  • Moreover, only one of the cell lines failed to express Smad4 [3].
  • Moreover, reporter assays of the Msx-2 promoter revealed an absolute requirement for Smad4 in fibroblasts and ES cells for activation [9].
  • These alterations are initiated by a dramatic expansion of the gastric epithelium where Smad4 is expressed [12].
  • These studies demonstrate that Smad4 functions as a tumor suppressor in the gastrointestinal tract and also provide a valuable model for screening factors that promote or prevent gastric tumorigenesis [12].
  • Here we show that Smad4+/- mice began to develop polyposis in the fundus and antrum when they were over 6 - 12 months old, and in the duodenum and cecum in older animals at a lower frequency [12].

Associations of Smad4 with chemical compounds

  • Gastro-intestinal tumorigenesis in Smad4 mutant mice [10].
  • During pre-implantation period, Smad2 hybridization signals were accumulated in the luminal and glandular epithelium at a basal level; Smad4 mRNA appeared in the epithelium with a little variation in hybridization signal intensity [13].
  • In amifostine-treated marrows, smad 2/3 and smad4 were not detected in the nucleus but were positive in the cytoplasm of megakaryocytes 10 days after irradiation [14].
  • Here we show that sphingosine 1-phosphate, independently of transforming growth factor beta secretion, induces a rapid phosphorylation of Smad3 on its C-terminal serine motif and induces its partnering with Smad4 and the translocation of the complex into the nucleus [15].
  • Regulation of steroidogenesis is disrupted in the Smad4 conditional knockout, leading to increased levels of serum progesterone [16].

Physical interactions of Smad4

  • A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A [17].

Regulatory relationships of Smad4


Other interactions of Smad4

  • Moreover, Smad2 or Smad3 with Smad4 enhanced the proteolytic pathway of p57(Kip2) [20].
  • After implantation, on day 5 of pregnancy, Smad2 signals were localized to the subluminal stroma surrounding the implanting blastocyst, and Smad4 mRNA were accumulated in the decidua near the luminal epithelium [13].
  • By deletion and mutational analyses we localized a Smad1/Smad4-binding site containing a GCAT motif, which showed similarity to other TGF-beta family responsive elements [21].
  • To assess the involvement of intracellular signaling protein Smads in regulating goldfish FSHbeta promoter, we first cloned full-length cDNAs for goldfish Smad2, Smad3, Smad4, and Smad7 from the pituitary [22].
  • Indeed, Nkx3.2 both fails to associate with the HDAC/Sin3A complex and represses target gene transcription in a cell line lacking Smad4, but it performs these functions if exogenous Smad4 is added to these cells [23].
  • These studies demonstrate essential roles of Smad4-mediated TGFbeta signaling in coupling bone formation and bone resorption and maintaining normal postnatal bone homeostasis [24].

Analytical, diagnostic and therapeutic context of Smad4

  • RT-PCR results showed that both Smad2 and Smad4 mRNA levels were rising during peri-implantatation [13].
  • In situ hybridization and semi-quantitative RT-PCR were employed to determine the temporal and spatial expression of Smad2 and Smad4 mRNA in mouse uterus during the oestrous cycle and early pregnancy [13].
  • These lesions share histological features of gastric polyps in aging mice with monoallelic null mutations in Smad4, which encodes the common transducer for transforming growth factor (TGF)-beta signaling [25].
  • Here, we show by loss of heterozygosity (LOH) analysis and immunohistochemistry (IHC) that, although the majority of the tumors appear at 9 months of age, somatic loss of the wild-type Smad4 allele occurs only at later stages of tumor progression [19].
  • RESULTS: We demonstrate that expression of Smad4/DPC4 in Capan-1 cells reduced anchorage-independent growth by more than 50%, and inhibited xenograft tumor growth [26].


  1. No effects of Smad2 (madh2) null mutation on malignant progression of intestinal polyps in Apc(delta716) knockout mice. Takaku, K., Wrana, J.L., Robertson, E.J., Taketo, M.M. Cancer Res. (2002) [Pubmed]
  2. Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc(Delta716) mouse intestinal polyps. Seno, H., Oshima, M., Ishikawa, T.O., Oshima, H., Takaku, K., Chiba, T., Narumiya, S., Taketo, M.M. Cancer Res. (2002) [Pubmed]
  3. Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. Xie, W., Mertens, J.C., Reiss, D.J., Rimm, D.L., Camp, R.L., Haffty, B.G., Reiss, M. Cancer Res. (2002) [Pubmed]
  4. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Takaku, K., Miyoshi, H., Matsunaga, A., Oshima, M., Sasaki, N., Taketo, M.M. Cancer Res. (1999) [Pubmed]
  5. SMAD4-deficient intestinal tumors recruit CCR1(+) myeloid cells that promote invasion. Kitamura, T., Kometani, K., Hashida, H., Matsunaga, A., Miyoshi, H., Hosogi, H., Aoki, M., Oshima, M., Hattori, M., Takabayashi, A., Minato, N., Taketo, M.M. Nat. Genet. (2007) [Pubmed]
  6. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. He, X.C., Zhang, J., Tong, W.G., Tawfik, O., Ross, J., Scoville, D.H., Tian, Q., Zeng, X., He, X., Wiedemann, L.M., Mishina, Y., Li, L. Nat. Genet. (2004) [Pubmed]
  7. A role for smad6 in development and homeostasis of the cardiovascular system. Galvin, K.M., Donovan, M.J., Lynch, C.A., Meyer, R.I., Paul, R.J., Lorenz, J.N., Fairchild-Huntress, V., Dixon, K.L., Dunmore, J.H., Gimbrone, M.A., Falb, D., Huszar, D. Nat. Genet. (2000) [Pubmed]
  8. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Takaku, K., Oshima, M., Miyoshi, H., Matsui, M., Seldin, M.F., Taketo, M.M. Cell (1998) [Pubmed]
  9. Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor beta-related signaling. Sirard, C., Kim, S., Mirtsos, C., Tadich, P., Hoodless, P.A., Itié, A., Maxson, R., Wrana, J.L., Mak, T.W. J. Biol. Chem. (2000) [Pubmed]
  10. Gastro-intestinal tumorigenesis in Smad4 mutant mice. Taketo, M.M., Takaku, K. Cytokine Growth Factor Rev. (2000) [Pubmed]
  11. 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]
  12. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Xu, X., Brodie, S.G., Yang, X., Im, Y.H., Parks, W.T., Chen, L., Zhou, Y.X., Weinstein, M., Kim, S.J., Deng, C.X. Oncogene (2000) [Pubmed]
  13. Expression of Smad2 and Smad4 in mouse uterus during the oestrous cycle and early pregnancy. Liu, G., Lin, H., Zhang, X., Li, Q., Wang, H., Qian, D., Ni, J., Zhu, C. Placenta (2004) [Pubmed]
  14. 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]
  15. Involvement of Smad signaling in sphingosine 1-phosphate-mediated biological responses of keratinocytes. Sauer, B., Vogler, R., von Wenckstern, H., Fujii, M., Anzano, M.B., Glick, A.B., Schäfer-Korting, M., Roberts, A.B., Kleuser, B. J. Biol. Chem. (2004) [Pubmed]
  16. Premature luteinization and cumulus cell defects in ovarian-specific Smad4 knockout mice. Pangas, S.A., Li, X., Robertson, E.J., Matzuk, M.M. Mol. Endocrinol. (2006) [Pubmed]
  17. A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A. Zhang, L., Duan, C.J., Binkley, C., Li, G., Uhler, M.D., Logsdon, C.D., Simeone, D.M. Mol. Cell. Biol. (2004) [Pubmed]
  18. Transforming growth factor-beta up-regulates the beta 5 integrin subunit expression via Sp1 and Smad signaling. Lai, C.F., Feng, X., Nishimura, R., Teitelbaum, S.L., Avioli, L.V., Ross, F.P., Cheng, S.L. J. Biol. Chem. (2000) [Pubmed]
  19. Smad4 haploinsufficiency in mouse models for intestinal cancer. Alberici, P., Jagmohan-Changur, S., De Pater, E., Van Der Valk, M., Smits, R., Hohenstein, P., Fodde, R. Oncogene (2006) [Pubmed]
  20. 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]
  21. Bone morphogenetic protein-2 (BMP-2) transactivates Dlx3 through Smad1 and Smad4: alternative mode for Dlx3 induction in mouse keratinocytes. Park, G.T., Morasso, M.I. Nucleic Acids Res. (2002) [Pubmed]
  22. 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]
  23. 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]
  24. Smad4 is required for maintaining normal murine postnatal bone homeostasis. Tan, X., Weng, T., Zhang, J., Wang, J., Li, W., Wan, H., Lan, Y., Cheng, X., Hou, N., Liu, H., Ding, J., Lin, F., Yang, R., Gao, X., Chen, D., Yang, X. J. Cell. Sci. (2007) [Pubmed]
  25. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Jenkins, B.J., Grail, D., Nheu, T., Najdovska, M., Wang, B., Waring, P., Inglese, M., McLoughlin, R.M., Jones, S.A., Topley, N., Baumann, H., Judd, L.M., Giraud, A.S., Boussioutas, A., Zhu, H.J., Ernst, M. Nat. Med. (2005) [Pubmed]
  26. Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human pancreatic cancer cells. Peng, B., Fleming, J.B., Breslin, T., Grau, A.M., Fojioka, S., Abbruzzese, J.L., Evans, D.B., Ayers, D., Wathen, K., Wu, T., Robertson, K.D., Chiao, P.J. Clin. Cancer Res. (2002) [Pubmed]
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