smad4 protein


Summary: A signal transducing adaptor protein and tumor suppressor protein. It forms a complex with activated RECEPTOR-REGULATED SMAD PROTEINS. The complex then translocates to the CELL NUCLEUS and regulates GENETIC TRANSCRIPTION of target GENES.

Top Publications

  1. Roth A, Delorenzi M, Tejpar S, Yan P, Klingbiel D, Fiocca R, et al. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst. 2012;104:1635-46 pubmed publisher
    ..Including molecular markers with independent prognostic value might allow more accurate prediction of prognosis than TNM staging alone. ..
  2. Yao G, Yin M, Lian J, Tian H, Liu L, Li X, et al. MicroRNA-224 is involved in transforming growth factor-beta-mediated mouse granulosa cell proliferation and granulosa cell function by targeting Smad4. Mol Endocrinol. 2010;24:540-51 pubmed publisher
    ..Such miRNA-mediated effects could be potentially used for regulation of reproductive processes or for treatment of reproductive disorders. ..
  3. Hoot K, Oka M, Han G, Bottinger E, Zhang Q, Wang X. HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion. J Clin Invest. 2010;120:3606-16 pubmed publisher
    ..Since Smad2 is often downregulated in human SCCs, our data suggest a therapeutic strategy of blocking HGF/c-Met activation for Smad2-deficient SCCs...
  4. Lee M, Lin S, Chang J, Schultz L, Heath J, Hsu L, et al. TGF-? induces TIAF1 self-aggregation via type II receptor-independent signaling that leads to generation of amyloid ? plaques in Alzheimer's disease. Cell Death Dis. 2010;1:e110 pubmed publisher
    ..Polymerized TIAF1 physically interacts with amyloid fibrils, which would favorably support plaque formation in vivo. ..
  5. Bornstein S, White R, Malkoski S, Oka M, Han G, Cleaver T, et al. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest. 2009;119:3408-19 pubmed publisher
    ..Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC...
  6. Liffers S, Maghnouj A, Munding J, Jackstadt R, Herbrand U, Schulenborg T, et al. Keratin 23, a novel DPC4/Smad4 target gene which binds 14-3-3?. BMC Cancer. 2011;11:137 pubmed publisher
  7. Long X, Miano J. Transforming growth factor-beta1 (TGF-beta1) utilizes distinct pathways for the transcriptional activation of microRNA 143/145 in human coronary artery smooth muscle cells. J Biol Chem. 2011;286:30119-29 pubmed publisher
    ..These results demonstrate a dual pathway for TGF-?1-induced transcription of miR143/145, thus revealing a novel mechanism underlying TGF-?1-induced human vascular SMC differentiation. ..
  8. Bianchi A, Gervasi M, Bakin A. Role of ?5-integrin in epithelial-mesenchymal transition in response to TGF-?. Cell Cycle. 2010;9:1647-59 pubmed
    ..Finally, depletion of ?5-integrin significantly reduced invasiveness of breast carcinoma cells. Thus, the ?5-integrin adhesions contribute to the TGF?-induced EMT and the tumorigenic potential of carcinoma cells. ..
  9. Chou J, Su H, Chen L, Liao Y, Hartman Frey C, Lai Y, et al. Promoter hypermethylation of FBXO32, a novel TGF-beta/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer. Lab Invest. 2010;90:414-25 pubmed publisher
    ..In conclusion, the novel tumor suppressor FBXO32 is epigenetically silenced in ovarian cancer cell lines with disrupted TGF-beta/SMAD4 signaling, and FBXO32 methylation status predicts survival in patients with ovarian cancer. ..

More Information


  1. Baraniskin A, Munding J, Schulmann K, Meier D, Porschen R, Arkenau H, et al. Prognostic value of reduced SMAD4 expression in patients with metastatic colorectal cancer under oxaliplatin-containing chemotherapy: a translational study of the AIO colorectal study group. Clin Colorectal Cancer. 2011;10:24-9 pubmed publisher
    ..Our data demonstrate the importance of reduced SMAD4 expression in patients with mCRC receiving chemotherapy with oxaliplatin and 5-FU. ..
  2. D Inzeo S, Nicolussi A, Donini C, Zani M, Mancini P, Nardi F, et al. A novel human Smad4 mutation is involved in papillary thyroid carcinoma progression. Endocr Relat Cancer. 2012;19:39-55 pubmed publisher
    ..Overall, our results demonstrate that the Smad4 C324Y mutation plays an important role in thyroid carcinogenesis and can be considered as a new prognostic and therapeutic target for thyroid cancer. ..
  3. Freeman T, Smith J, Chen X, Washington M, Roland J, Means A, et al. Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of ?-catenin. Gastroenterology. 2012;142:562-571.e2 pubmed publisher
    ..Transcription of ?-catenin is inhibited by BMP signaling to Smad4. These findings provide important information about the interaction among transforming growth factor ?, BMP, and Wnt signaling pathways in progression of CRC. ..
  4. Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet. 2011;44:85-8 pubmed publisher
    ..We also observed decreased expression of downstream TGF-? target genes, supporting the idea of impaired TGF-?-mediated transcriptional control in individuals with Myhre syndrome...
  5. Caputo V, Cianetti L, Niceta M, Carta C, Ciolfi A, Bocchinfuso G, et al. A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome. Am J Hum Genet. 2012;90:161-9 pubmed publisher
  6. Tang M, Wang Y, Guo S, Han S, Wang D. CSMD1 exhibits antitumor activity in A375 melanoma cells through activation of the Smad pathway. Apoptosis. 2012;17:927-37 pubmed publisher
    ..Furthermore, we found that CSMD1 can interact with Smad3, activate Smad1, Smad2, and Smad3, and increase the expression of Smad4. These results might prove helpful for the development of novel therapies for melanoma treatment. ..
  7. Mao X, Debenedittis P, Sun Y, Chen J, Yuan K, Jiao K, et al. Vascular smooth muscle cell Smad4 gene is important for mouse vascular development. Arterioscler Thromb Vasc Biol. 2012;32:2171-7 pubmed publisher
    ..These studies provide important insight into the role of Smad4 and its upstream Smads in regulating SMC function and vascular development of mice. ..
  8. Hahn J, Falck V, Jirik F. Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice. J Clin Invest. 2011;121:4030-42 pubmed publisher
    ..Thus, our data indicate that a chronic increase in gut Th17 cell activity can be associated with the development of premalignant lesions of the gastroduodenal region. ..
  9. Papageorgis P, Cheng K, Ozturk S, Gong Y, Lambert A, Abdolmaleky H, et al. Smad4 inactivation promotes malignancy and drug resistance of colon cancer. Cancer Res. 2011;71:998-1008 pubmed publisher
    ..These findings are also consistent with targeting TGF?-induced auxiliary pathways, such as MEK-ERK, and p38-MAPK and the glycolytic cascade, in SMAD4-deficient tumors as attractive strategies for therapeutic intervention. ..
  10. Ali N, McKay M, Molloy M. Proteomics of Smad4 regulated transforming growth factor-beta signalling in colon cancer cells. Mol Biosyst. 2010;6:2332-8 pubmed publisher
    ..Our proteomic screen has identified new Smad4 dependent and independent TGF-? responses in colon carcinoma cells. ..
  11. Leeper N, Raiesdana A, Kojima Y, Chun H, Azuma J, Maegdefessel L, et al. MicroRNA-26a is a novel regulator of vascular smooth muscle cell function. J Cell Physiol. 2011;226:1035-43 pubmed publisher
    ..MicroRNA-26a represents an important new regulator of SMC biology and a potential therapeutic target in AAA disease. ..
  12. Dupont S, Inui M, Newfeld S. Regulation of TGF-? signal transduction by mono- and deubiquitylation of Smads. FEBS Lett. 2012;586:1913-20 pubmed publisher
    ..Here we summarize and discuss recent work on Smad mono- and deubiquitylation. ..
  13. Zhong H, Wang H, Yang S, Zhong J, Wang T, Wang C, et al. Targeting Smad4 links microRNA-146a to the TGF-beta pathway during retinoid acid induction in acute promyelocytic leukemia cell line. Int J Hematol. 2010;92:129-35 pubmed publisher
    ..These data suggested that miR-146a might influence proliferation of APL cells through TGF-beta1/Smad signal transduction pathway during ATRA induction. ..
  14. Ding Z, Wu C, Chu G, Xiao Y, Ho D, Zhang J, et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011;470:269-73 pubmed publisher
    ..This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans. ..
  15. Korc M. Smad4: gatekeeper gene in head and neck squamous cell carcinoma. J Clin Invest. 2009;119:3208-11 pubmed publisher
    ..These findings point to a novel function for Smad4 as a guardian gene that maintains genomic stability. ..
  16. Xiao B, Zhu E, Li N, Lu D, Li W, Li B, et al. Increased miR-146a in gastric cancer directly targets SMAD4 and is involved in modulating cell proliferation and apoptosis. Oncol Rep. 2012;27:559-66 pubmed publisher
    ..miR-146a could serve as a potential biomarker and therapeutic target against gastric cancer. ..
  17. D Inzeo S, Nicolussi A, Ricci A, Mancini P, Porcellini A, Nardi F, et al. Role of reduced expression of SMAD4 in papillary thyroid carcinoma. J Mol Endocrinol. 2010;45:229-44 pubmed publisher
    ..Our data demonstrated for the first time that these cells showed a strong reduction in the level of SMAD4 protein, which was responsible for an alteration of TGF? signaling and for some of the TGF?-mediated biological ..
  18. Petersen M, Pardali E, van der Horst G, Cheung H, van den Hoogen C, van der Pluijm G, et al. Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene. 2010;29:1351-61 pubmed publisher
    ..Thus, Smad2 and Smad3 differentially affect breast cancer bone metastasis formation in vivo...
  19. Stinchfield M, Takaesu N, Quijano J, Castillo A, Tiusanen N, Shimmi O, et al. Fat facets deubiquitylation of Medea/Smad4 modulates interpretation of a Dpp morphogen gradient. Development. 2012;139:2721-9 pubmed publisher
    ..This study supports the hypothesis that the control of cellular responsiveness to TGF? signals at the level of Smad4 ubiquitylation is a conserved mechanism required for proper implementation of a morphogen gradient. ..
  20. Häger M, Pedersen C, Larsen M, Andersen M, Hother C, Grønbæk K, et al. MicroRNA-130a-mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-?1 stimulation in granulocytic precursors. Blood. 2011;118:6649-59 pubmed publisher
    ..The transcript for Smad4 is present throughout neutrophil maturation, but Smad4 protein is undetectable in the most immature cells, where miR-130a is highly expressed...
  21. Ottenhof N, Morsink F, Ten Kate F, Van Noorden C, Offerhaus G. Multivariate analysis of immunohistochemical evaluation of protein expression in pancreatic ductal adenocarcinoma reveals prognostic significance for persistent Smad4 expression only. Cell Oncol (Dordr). 2012;35:119-26 pubmed publisher
    ..It underscores the importance to standardize the methods used for the application of immunohistochemistry in prognostic studies. ..
  22. Sayeed A, Meng Z, Luciani G, Chen L, Bennington J, Dairkee S. Negative regulation of UCP2 by TGF? signaling characterizes low and intermediate-grade primary breast cancer. Cell Death Dis. 2010;1:e53 pubmed publisher
  23. Hesling C, Fattet L, Teyre G, Jury D, Gonzalo P, Lopez J, et al. Antagonistic regulation of EMT by TIF1? and Smad4 in mammary epithelial cells. EMBO Rep. 2011;12:665-72 pubmed publisher
    ..This study shows the molecular relationship between TIF1? and Smad4 in TGF-? signalling and EMT. ..
  24. Isaksson Mettävainio M, Palmqvist R, Dahlin A, Van Guelpen B, Rutegård J, Oberg A, et al. High SMAD4 levels appear in microsatellite instability and hypermethylated colon cancers, and indicate a better prognosis. Int J Cancer. 2012;131:779-88 pubmed publisher
    ..The novel findings that high SMAD4 expression predicts a better prognosis suggests that SMAD4 immunohistochemistry could constitute a prognostic marker in combination with CIMP and MSI screening status. ..
  25. Wang J, Song Y, Zhang Y, Xiao H, Sun Q, Hou N, et al. Cardiomyocyte overexpression of miR-27b induces cardiac hypertrophy and dysfunction in mice. Cell Res. 2012;22:516-27 pubmed publisher
    ..The results of our study demonstrate that TGF-?1-regulated miR-27b is involved in the regulation of cardiac hypertrophy, and validate miR-27b as an efficient therapeutic target for cardiac diseases. ..
  26. Ahn B, Jang S, Paik S, Lee K. Smad4 may help to identify a subset of colorectal cancer patients with early recurrence after curative therapy. Hepatogastroenterology. 2011;58:1933-6 pubmed publisher
    ..b>Smad4 protein was expressed in 61.5% (24/39), 53.1% (77/145), 41.3% (78/189) and 34...
  27. Baburajendran N, Jauch R, Tan C, Narasimhan K, Kolatkar P. Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers. Nucleic Acids Res. 2011;39:8213-22 pubmed publisher
  28. Gao Y, Yang G, Weng T, Du J, Wang X, Zhou J, et al. Disruption of Smad4 in odontoblasts causes multiple keratocystic odontogenic tumors and tooth malformation in mice. Mol Cell Biol. 2009;29:5941-51 pubmed publisher
    ..These findings provide insight into the genetic basis underlying KCOTs and have important implications for new directions in KCOT treatment...
  29. Liu R, Zhou Z, Huang J, Chen C. PMEPA1 promotes androgen receptor-negative prostate cell proliferation through suppressing the Smad3/4-c-Myc-p21 Cip1 signaling pathway. J Pathol. 2011;223:683-94 pubmed publisher
    ..Finally, we found that PMEPA1 is overexpressed in a subset of prostate cancer cell lines and tumours. These findings suggest that PMEPA1 may promote AR-negative prostate cancer cell proliferation through p21. ..
  30. Xu X, Ehdaie B, Ohara N, Yoshino T, Deng C. Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice. Oncogene. 2010;29:674-86 pubmed publisher
  31. Zhang Y, Fan K, Sun Q, Chen A, Shen W, Zhao Z, et al. Functional screening for miRNAs targeting Smad4 identified miR-199a as a negative regulator of TGF-? signalling pathway. Nucleic Acids Res. 2012;40:9286-97 pubmed publisher
    ..In conclusion, our functional screening uncovers multiple miRNAs that regulate the cellular responsiveness to TGF-? signalling and reveals important roles of miR-199a in gastric cancer by directly targeting Smad4. ..
  32. Latchford A, Neale K, Phillips R, Clark S. Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome. Dis Colon Rectum. 2012;55:1038-43 pubmed publisher
    ..Extraintestinal features are common. Gastrointestinal surveillance is safe. Most colonic polyps are right sided, and detecting dysplasia is uncommon. Carpeting polyps are of particular concern. ..
  33. Yang G, Yang X. Smad4-mediated TGF-beta signaling in tumorigenesis. Int J Biol Sci. 2010;6:1-8 pubmed
  34. Warmflash A, Zhang Q, Sorre B, Vonica A, Siggia E, Brivanlou A. Dynamics of TGF-? signaling reveal adaptive and pulsatile behaviors reflected in the nuclear localization of transcription factor Smad4. Proc Natl Acad Sci U S A. 2012;109:E1947-56 pubmed publisher
    ..Thus, R-Smads relay graded information about ligand levels that is integrated with intrinsic temporal control reflected in Smad4 into the active signaling complex...
  35. Handra Luca A, Olschwang S, Flejou J. SMAD4 protein expression and cell proliferation in colorectal adenocarcinomas. Virchows Arch. 2011;459:511-9 pubmed publisher
    ..Although the advantage of immunohistochemistry is high throughput, our results allow only an initial evaluation, and subsequent studies, including genetic analyses, are required. ..
  36. Danielsson K, Wahlin Y, Coates P, Nylander K. Increased expression of Smad proteins, and in particular Smad3, in oral lichen planus compared to normal oral mucosa. J Oral Pathol Med. 2010;39:639-44 pubmed publisher
    ..Changes in the TGF-? pathway related to EMT are seen in the very earliest stages of oral malignancy and become more severe as lesions progress. ..
  37. Geraldo M, Yamashita A, Kimura E. MicroRNA miR-146b-5p regulates signal transduction of TGF-? by repressing SMAD4 in thyroid cancer. Oncogene. 2012;31:1910-22 pubmed publisher
    ..Our results confirm the oncogenic role of miR-146b-5p in thyroid follicular cells and contribute to knowledge regarding the modulation of TGF-? signal transduction by miRNAs in PTCs. ..
  38. He S, Zhao Z, Wang Y, Zhao J, Wang L, Hou F, et al. Reduced expression of SMAD4 in gliomas correlates with progression and survival of patients. J Exp Clin Cancer Res. 2011;30:70 pubmed publisher
    ..SMAD4 may play an inhibitive role during the development of glioma and may be a potential prognosis predictor of glioma. ..
  39. Langeveld D, van Hattem W, de Leng W, Morsink F, ten Kate F, Giardiello F, et al. SMAD4 immunohistochemistry reflects genetic status in juvenile polyposis syndrome. Clin Cancer Res. 2010;16:4126-34 pubmed publisher
    ..Instead, different routes to neoplasia in JPS caused by germline SMAD4 mutation seem to be operative, including somatic loss of SMAD4 and p53 inactivation without somatic loss of SMAD4. ..
  40. Fei T, Xia K, Li Z, Zhou B, Zhu S, Chen H, et al. Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination. Genome Res. 2010;20:36-44 pubmed publisher
    ..Combined with computational analysis, our results suggest that SMAD-mediated BMP signaling balances self-renewal versus differentiation by modulating a set of developmental regulators. ..
  41. Zhang B, Halder S, Kashikar N, Cho Y, Datta A, Gorden D, et al. Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology. 2010;138:969-80.e1-3 pubmed publisher
    ..Loss of Smad4 might underlie the functional shift of TGF-beta from a tumor suppressor to a tumor promoter; inhibitors of TGF-beta signaling might be developed as CRC therapeutics. ..
  42. Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A, Grady W, et al. Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell. 2007;11:229-43 pubmed
    ..Our findings suggest that the sequence, as well as the context, in which these critical mutations are acquired helps determine the ensuing pathology. ..
  43. Tian X, Du H, Fu X, Li K, Li A, Zhang Y. Smad4 restoration leads to a suppression of Wnt/beta-catenin signaling activity and migration capacity in human colon carcinoma cells. Biochem Biophys Res Commun. 2009;380:478-83 pubmed publisher
    ..The data suggested that restoration of Smad4 in Smad4-deficient cells may provide a potential therapeutic strategy for intervention of colon cancer migration and metastasis. ..
  44. Levy L, Howell M, Das D, Harkin S, Episkopou V, Hill C. Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Mol Cell Biol. 2007;27:6068-83 pubmed
    ..Reintroduction of wild-type Arkadia restores TGF-beta-induced Smad3/Smad4-dependent transcription and SnoN degradation in these cells, raising the possibility that loss of Arkadia function may be relevant in cancer. ..
  45. Ko S, Chung I, Xu X, Oka S, Zhao H, Cho E, et al. Smad4 is required to regulate the fate of cranial neural crest cells. Dev Biol. 2007;312:435-47 pubmed
    ..Taken together, our data show that TGF-beta/BMP signals rely on Smad-dependent pathways in the ectomesenchyme to mediate epithelial-mesenchymal interactions that control craniofacial organogenesis...
  46. Aitchison A, Veerakumarasivam A, Vias M, Kumar R, Hamdy F, Neal D, et al. Promoter methylation correlates with reduced Smad4 expression in advanced prostate cancer. Prostate. 2008;68:661-74 pubmed publisher
    ..This indicates that epigenetic changes affect the expression of the Smad4 protein in prostate cancer and points to methylation of the promoter as a novel marker of and contributor to the ..
  47. Koinuma D, Tsutsumi S, Kamimura N, Imamura T, Aburatani H, Miyazono K. Promoter-wide analysis of Smad4 binding sites in human epithelial cells. Cancer Sci. 2009;100:2133-42 pubmed publisher
    ..Our findings revealed some general characteristics of Smad4 binding regions, and provide resources for examining the role of Smad4 in epithelial cells and cancer pathogenesis. ..
  48. Nie X, Deng C, Wang Q, Jiao K. Disruption of Smad4 in neural crest cells leads to mid-gestation death with pharyngeal arch, craniofacial and cardiac defects. Dev Biol. 2008;316:417-30 pubmed publisher
    ..Taken together, these findings provide compelling genetic evidence that Smad4-mediated activities of TGFbeta/BMP signals are essential for appropriate NCC development. ..
  49. Barros R, Pereira B, Duluc I, Azevedo M, Mendes N, Camilo V, et al. Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines. J Pathol. 2008;215:411-20 pubmed publisher
    ..In conclusion, we identified for the first time that the BMP pathway is active in intestinal metaplasia and that BMP2 and BMP4 regulate CDX2 expression and promote intestinal differentiation through the canonical signal transducers. ..
  50. Lönn P, Morén A, Raja E, Dahl M, Moustakas A. Regulating the stability of TGFbeta receptors and Smads. Cell Res. 2009;19:21-35 pubmed publisher
    ..We highlight links between these mechanisms and human diseases, such as tissue fibrosis and cancer. ..
  51. Zapatka M, Zboralski D, Radacz Y, Bockmann M, Arnold C, Schöneck A, et al. Basement membrane component laminin-5 is a target of the tumor suppressor Smad4. Oncogene. 2007;26:1417-27 pubmed
    ..These data define the expression control of an essential BM component as a novel function for the tumor suppressor Smad4. ..
  52. Chan M, Huang Y, Hartman Frey C, Kuo C, Deatherage D, Qin H, et al. Aberrant transforming growth factor beta1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer. Neoplasia. 2008;10:908-19 pubmed
    ..Given the emerging role of ADAMs family proteins in growth factor regulation in normal cells, we suggest that epigenetic dysregulation of ADAM19 may contribute to the neoplastic process in ovarian cancer. ..
  53. Matak P, Chaston T, Chung B, Srai S, McKie A, Sharp P. Activated macrophages induce hepcidin expression in HuH7 hepatoma cells. Haematologica. 2009;94:773-80 pubmed publisher
    ..Our data suggest that the interleukin-1beta and bone morphogenetic protein signaling pathways are central to the regulation of HAMP expression by macrophages in this co-culture model. ..