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Gene Review

SMAD5  -  SMAD family member 5

Homo sapiens

Synonyms: DWFC, Dwfc, JV5-1, MAD homolog 5, MADH5, ...
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Disease relevance of SMAD5


High impact information on SMAD5

  • Smad5 is dispensable for adult murine hematopoiesis [5].
  • 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 [5].
  • Furthermore, phenotypic characterization of the stem cell compartment revealed normal numbers of primitive lin(-)Sca-1(+)c-Kit(+) (LSK) cells in Smad5(-)(/)(-) BM [5].
  • More importantly, profoundly increased frequency of HPP-CFCs, featured with a gene-dosage effect, was detected within day 6 Smad5(-/-) EBs compared with the wild type [6].
  • Yeast 2-hybrid interaction assays reveal the lack of physical interactions between SMAD5beta and SMAD5 or SMAD4 [1].

Biological context of SMAD5


Anatomical context of SMAD5

  • Differential expression of a novel C-terminally truncated splice form of SMAD5 in hematopoietic stem cells and leukemia [1].
  • In contrast to SMAD5, DAMS expression is not readily detectable in adult and fetal tissues [8].
  • We further examined whether the up-regulated Smad5 was related to apoptosis of gastric epithelial cells induced by H. pylori [2].
  • METHODS: Yeast 2-hybrid technology was used to screen a complementary DNA library, constructed from human adult articular cartilage, for molecular binding partners of Smad5, a major intracellular mediator of BMP signaling [10].
  • RESULTS: In the presence of BMP-2, chondrocytes over-expressing BMP-activated Smadl or Smad5 showed significant enhancement of luciferase production compared with that seen with BMP alone [11].

Associations of SMAD5 with chemical compounds


Physical interactions of SMAD5


Regulatory relationships of SMAD5

  • Smad5 belongs to the receptor-activated Smad that function as intracellular signal transducers for transforming growth factor-beta superfamily [13].
  • Further, individual genes, TNF-alpha induced protein 6 (TNFaip6) and membrane-spanning 4-domains, subfamily A (ms4a) were found to be upregulated in PSC while similar to Mothers against decapentaplegic homolog 5 (SMAD 5) was downregulated [14].

Other interactions of SMAD5


Analytical, diagnostic and therapeutic context of SMAD5

  • Semiquantitative PCR suggests that the stoichiometry between SMAD5 and DAMS transcripts ranges between 15 and 120 in normal and malignant hematopoietic cells [8].
  • Using confocal microscopy, we here show for the first time that immunofluorescent labeling of Smad5, one of the Smad proteins associated with BMP signaling, colocalizes with the mitochondrion-specific probe MitoTracker, demonstrating a mitochondrial distribution of Smad5 in non-stimulated chondroprogenitor cells [18].
  • We showed by reverse transcriptase polymerase chain reaction that the RNA from one homologue gene, Smad5, was present in the immortalized myeloid leukemia cell lines, KG1 and HL60, in bone marrow mononuclear and polymorphonuclear cells, as well as in purified CD34+ bone marrow cells [19].


  1. Differential expression of a novel C-terminally truncated splice form of SMAD5 in hematopoietic stem cells and leukemia. Jiang, Y., Liang, H., Guo, W., Kottickal, L.V., Nagarajan, L. Blood (2000) [Pubmed]
  2. Up-regulated Smad5 mediates apoptosis of gastric epithelial cells induced by Helicobacter pylori infection. Nagasako, T., Sugiyama, T., Mizushima, T., Miura, Y., Kato, M., Asaka, M. J. Biol. Chem. (2003) [Pubmed]
  3. Inhibition of Smad5 in human hematopoietic progenitors blocks erythroid differentiation induced by BMP4. Fuchs, O., Simakova, O., Klener, P., Cmejlova, J., Zivny, J., Zavadil, J., Stopka, T. Blood Cells Mol. Dis. (2002) [Pubmed]
  4. Analysis of the Smad5 gene in hematological malignancies. Ikezoe, T., Takeuchi, S., Kobayashi, M., Taguchi, H. Am. J. Hematol. (1999) [Pubmed]
  5. 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]
  6. Disruption of Smad5 gene leads to enhanced proliferation of high-proliferative potential precursors during embryonic hematopoiesis. Liu, B., Sun, Y., Jiang, F., Zhang, S., Wu, Y., Lan, Y., Yang, X., Mao, N. Blood (2003) [Pubmed]
  7. Localization of SMAD5 and its evaluation as a candidate myeloid tumor suppressor. Hejlik, D.P., Kottickal, L.V., Liang, H., Fairman, J., Davis, T., Janecki, T., Sexton, D., Perry, W., Tavtigian, S.V., Teng, D.H., Nagarajan, L. Cancer Res. (1997) [Pubmed]
  8. An antisense transcript to SMAD5 expressed in fetal and tumor tissues. Zavadil, J., Svoboda, P., Liang, H., Kottickal, L.V., Nagarajan, L. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  9. SMAD5 gene expression, rearrangements, copy number, and amplification at fragile site FRA5C in human hepatocellular carcinoma. Zimonjic, D.B., Durkin, M.E., Keck-Waggoner, C.L., Park, S.W., Thorgeirsson, S.S., Popescu, N.C. Neoplasia (2003) [Pubmed]
  10. Jun activation domain-binding protein 1 binds Smad5 and inhibits bone morphogenetic protein signaling. Haag, J., Aigner, T. Arthritis Rheum. (2006) [Pubmed]
  11. Smad-Runx interactions during chondrocyte maturation. Leboy, P., Grasso-Knight, G., D'Angelo, M., Volk, S.W., Lian, J.V., Drissi, H., Stein, G.S., Adams, S.L. The Journal of bone and joint surgery. American volume. (2001) [Pubmed]
  12. Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. Nishimura, R., Kato, Y., Chen, D., Harris, S.E., Mundy, G.R., Yoneda, T. J. Biol. Chem. (1998) [Pubmed]
  13. Smad5: signaling roles in hematopoiesis and osteogenesis. Liu, B., Mao, N. Int. J. Biochem. Cell Biol. (2004) [Pubmed]
  14. Gene expression by PBMC in primary sclerosing cholangitis: Evidence for dysregulation of immune mediated genes. Aoki, C.A., Dawson, K., Kenny, T.P., Gershwin, M.E., Bowlus, C.L. Clin. Dev. Immunol. (2006) [Pubmed]
  15. Frequency of Smad gene mutations in human cancers. Riggins, G.J., Kinzler, K.W., Vogelstein, B., Thiagalingam, S. Cancer Res. (1997) [Pubmed]
  16. Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth factor-beta receptor. Ulloa, L., Tabibzadeh, S. J. Biol. Chem. (2001) [Pubmed]
  17. Smad5, a tumor suppressor candidate at 5q31.1, is hemizygously lost and not mutated in the retained allele in human leukemia cell line HL60. Zavadil, J., Brezinová, J., Svoboda, P., Zemanová, Z., Michalová, K. Leukemia (1997) [Pubmed]
  18. Mitochondrial localization of Smad5 in a human chondrogenic cell line. Jüllig, M., Stott, N.S. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  19. The Smad5 gene is involved in the intracellular signaling pathways that mediate the inhibitory effects of transforming growth factor-beta on human hematopoiesis. Bruno, E., Horrigan, S.K., Van Den Berg, D., Rozler, E., Fitting, P.R., Moss, S.T., Westbrook, C., Hoffman, R. Blood (1998) [Pubmed]
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