Abstract

Transforming growth factor beta (TGF-β) plays a crucial role and takes part in many processes in the human body both in physiology and pathology. This cytokine is involved in angiogenesis, regulates apoptosis and stimulates divisions of cells, such as hepatocytes, lymphocytes or hematopoietic cells. SMAD proteins family is a unique group of particles responsible for transducting the signal induced by TGF-β into the nucleus. This molecules, after receiving a signal from activated TGF-β, act on transcription factors in the nucleus, leading directly to the expression of the corresponding genes. According to current knowledge, disturbances in the functioning of SMAD proteins are present in a number of diseases. The reduced expression was observed, for example in cardiovascular diseases such as primary pulmonary hypertension or myocardial infarction, autoimmune diseases for instance systemic lupus erythematosus and multiple sclerosis, Alzheimer’s disease or osteoporosis. The latest clinical data showed the presence of mutations in SMAD proteins in cancerogenesis. Mutation of SMAD-4 protein can be detected in half of the patients with pancreatic cancer, 20% of patients with colorectal cancer and 10% of patients with lung cancer. However, mutation in SMAD-2 protein was observed in 7% of both patients with colorectal cancer and lung cancer. On the basis of numerous works, SMAD protein expression would be valuable prognostic factor in some of neoplastic diseases.

References

• 1. Antony M.L., Nair R., Sebastian P., Karunagaran D.: Changes inexpression, and/or mutations in TGF-β receptors (TGF-β RI andTGF-β RII) and Smad 4 in human ovarian tumors. J. Cancer Res. Clin.Oncol., 2010; 136: 351-361
  Google Scholar
• 2. Arnulf B., Villemain A., Nicot C., Mordelet E., Charneau P., KersualJ., Zermati Y., Mauviel A., Bazarbachi A., Hermine O.: Human T-celllymphotropic virus oncoprotein Tax represses TGF-β1 signaling inhuman T cells via c-Jun activation: a potential mechanism of HTLV-Ileukemogenesis. Blood, 2002; 100: 4129-4138
  Google Scholar
• 3. Attisano L., Wrana J.L.: Smads as transcriptional co-modulators.Curr. Opin. Cell Biol., 2000; 12: 235-243
  Google Scholar
• 4. Bakin A.V., Rinehart C., Tomlinson A.K., Arteaga C.L.: p38 mitogen-activatedprotein kinase is required for TGFβ-mediated fibroblastictransdifferentiation and cell migration. J. Cell. Sci., 2002;115: 3193-3206
  Google Scholar
• 5. Bakin A.V., Tomlinson A.K., Bhowmick N.A., Moses H.L., ArteagaC.L.: Phosphatidylinositol 3-kinase function is required for transforminggrowth factor β-mediated epithelial to mesenchymal transitionand cell migration. J. Biol. Chem., 2000; 275: 36803-36810
  Google Scholar
• 6. Bakkebø M., Huse K., Hilden V.I., Smeland E.B., Oksvold M.P.:TGF-β-induced growth inhibition in B-cell lymphoma correlateswith Smad1/5 signalling and constitutively active p38 MAPK. BMCImmunol., 2010; 11: 57
  Google Scholar
• 7. Bhowmick N.A., Ghiassi M., Bakin A., Aakre M., LundquistC.A., Engel M.E., Arteaga C.L., Moses H.L.: Transforming growthfactor-β1 mediates epithelial to mesenchymal transdifferentiationthrough a RhoA-dependent mechanism. Mol. Biol. Cell.,2001; 12: 27-36
  Google Scholar
• 8. Bierie B., Moses H.L.: Tumour microenvironment: TGFβ: the molecularJekyll and Hyde of cancer. Nat. Rev. Cancer, 2006; 6: 506-520
  Google Scholar
• 9. Bruna A., Darken R.S., Rojo F., Ocaña A., Peñuelas S., Arias A., ParisR., Tortosa A., Mora J., Baselga J., Seoane J.: High TGFβ-Smad activityconfers poor prognosis in glioma patients and promotes cell proliferationdepending on the methylation of the PDGF-B gene. CancerCell, 2007; 11: 147-160
  Google Scholar
• 10. Chan M.W., Huang Y.W., Hartman-Frey C., Kuo C.T., DeatherageD., Qin H., Cheng A.S., Yan P.S., Davuluri R.V., Huang T.H., NephewK.P., Lin H.J.: Aberrant transforming growth factor β1 signalingand SMAD4 nuclear translocation confer epigenetic repression ofADAM19 in ovarian cancer. Neoplasia, 2008; 10: 908-919
  Google Scholar
• 11. Cheifetz S., Weatherbee J.A., Tsang M.L., Anderson J.K., MoleJ.E., Lucas R., Massagué J.: The transforming growth factor-β system,a complex pattern of cross-reactive ligands and receptors.Cell, 1987; 48: 409-415
  Google Scholar
• 12. Chen G., Ghosh P., Osawa H., Sasaki C.Y., Rezanka L., Yang J.,O›Farrell T.J., Longo D.L.: Resistance to TGF-β1 correlates with aberrantexpression of TGF-β receptor II in human B-cell lymphomacell lines. Blood, 2007; 109: 5301-5307
  Google Scholar
• 13. Derynck R., Feng X.H.: TGF-β receptor signaling. Biochim. Biophys.Acta, 1997; 1333: F105-F150
  Google Scholar
• 14. Engel M.E., McDonnell M.A., Law B.K., Moses H.L.: InterdependentSMAD and JNK signaling in transforming growth factor-β-mediated transcription. J. Biol. Chem., 1999; 274: 37413-37420
  Google Scholar
• 15. Eppert K., Scherer S.W., Ozcelik H., Pirone R., Hoodless P., Kim H.,Tsui L.C., Bapat B., Gallinger S., Andrulis I.L., Thomsen G.H., WranaJ.L., Attisano L.: MADR2 maps to 18q21 and encodes a TGFβ-regulatedMAD-related protein that is functionally mutated in colorectal carcinoma.Cell, 1996; 86: 543-552
  Google Scholar
• 16. Flanders K.C., Burmester J.K.: Medical applications of transforminggrowth factor-β. Clin. Med. Res., 2003; 1: 13-20
  Google Scholar
• 17. Furukawa T.: Molecular pathology of pancreatic cancer: implicationsfor molecular targeting therapy. Clin. Gastroenterol. Hepatol.;2009; 7 (Suppl. 11): S35-S39
  Google Scholar
• 18. Gingery A., Bradley E.W., Pederson L., Ruan M., Horwood N.J.,Oursler M.J.: TGF-β coordinately activates TAK1/MEK/AKT/NFkBand SMAD pathways to promote osteoclast survival. Exp. Cell Res.,2008; 314: 2725-2738
  Google Scholar
• 19. Hahn S.A., Hoque A.T., Moskaluk C.A., da Costa L.T., Schutte M.,Rozenblum E., Seymour A.B., Weinstein C.L., Yeo C.J., Hruban R.H.,Kern S.E.: Homozygous deletion map at 18q21.1 in pancreatic cancer.Cancer Res., 1996; 56: 490-494
  Google Scholar
• 20. Han S.U., Kim H.T., Seong D.H., Kim Y.S., Park Y.S., Bang Y.J.,Yang H.K., Kim S.J.: Loss of the Smad3 expression increases susceptibilityto tumorigenicity in human gastric cancer. Oncogene,2004; 23: 1333-1341
  Google Scholar
• 21. Hata A., Lagna G., Massagué J., Hemmati-Brivanlou A.: Smad6inhibits BMP/Smad1 signaling by specifically competing with theSmad4 tumor suppressor. Genes Dev., 1998; 12: 186-197
  Google Scholar
• 22. Imai Y., Kurokawa M., Izutsu K., Hangaishi A., Maki K., Ogawa S.,Chiba S., Mitani K., Hirai H.: Mutations of the Smad4 gene in acutemyelogeneous leukemia and their functional implications in leukemogenesis.Oncogene, 2001; 20: 88-96
  Google Scholar
• 23. Jakubowiak A., Pouponnot C., Berguido F., Frank R., Mao S., MassagueJ., Nimer S.D.: Inhibition of the transforming growth factorβ1 signaling pathway by the AML1/ETO leukemia-associated fusionprotein. J. Biol. Chem., 2000; 275: 40282-40287
  Google Scholar
• 24. Jeon H.S., Dracheva T., Yang S.H., Meerzaman D., Fukuoka J.,Shakoori A., Shilo K., Travis W.D., Jen J.: SMAD6 contributes to patientsurvival in non-small cell lung cancer and its knockdown reestablishesTGF-β homeostasis in lung cancer cells. Cancer Res.,2008; 68: 9686-9692
  Google Scholar
• 25. Kavsak P., Rasmussen R.K., Causing C.G., Bonni S., Zhu H., ThomsenG.H., Wrana J.L.: Smad7 binds to Smurf2 to form an E3 ubiquitinligase that targets the TGFβ receptor for degradation. Mol. Cell.,2000; 6: 1365-1375
  Google Scholar
• 26. Kennedy B.A., Deatherage D.E., Gu F., Tang B., Chan M.W., NephewK.P., Huang T.H., Jin V.X.: ChIP-seq defined genome-wide map ofTGFβ/SMAD4 targets: implications with clinical outcome of ovariancancer. PLoS One, 2011; 6: e22606
  Google Scholar
• 27. Kim S.G., Jong H.S., Kim T.Y., Lee J.W., Kim N.K., Hong S.H., BangY.J.: Transforming growth factor-b1 induces apoptosis through Fasligand-independent activation of the Fas death pathway in humangastric SNU-620 carcinoma cells. Mol. Biol. Cell, 2004; 15: 420-434
  Google Scholar
• 28. Kjellman C., Olofsson S.P., Hansson O., Von Schantz T., LindvallM., Nilsson I., Salford L.G., Sjögren H.O., Widegren B.: Expression ofTGF-β isoforms, TGF-β receptors, and Smad molecules at differentstages of human glioma. Int. J. Cancer, 2000; 89: 251-258
  Google Scholar
• 29. Klimaszewska-Wiśniewska A., Nowak J.M., Żuryń A., Grzanka A.:Udział białek Rho w regulacji postępu fazy G1 cyklu komórkowego.Postępy Hig. Med. Dośw., 2013; 67: 15-25
  Google Scholar
• 30. Krzemień S., Knapczyk P.: Aktualne poglądy dotyczące znaczeniatransformującego czynnika wzrostu beta (TGF-beta) w patogenezieniektórych stanów chorobowych. Wiad. Lek., 2005; 58: 536-539
  Google Scholar
• 31. Ku J.L., Park S.H., Yoon K.A., Shin Y.K., Kim K.H., Choi J.S., KangH.C., Kim I.J., Han I.O., Park J.G.: Genetic alterations of the TGF-βsignaling pathway in colorectal cancer cell lines: a novel mutationin Smad3 associated with the inactivation of TGF-β-induced transcriptionalactivation. Cancer Lett., 2007; 247: 283-292
  Google Scholar
• 32. Lamouille S., Derynck R.: Cell size and invasion in TGF-β-inducedepithelial to mesenchymal transition is regulated by activation ofthe mTOR pathway. J. Cell Biol., 2007; 178: 437-451
  Google Scholar
• 33. Lee D.K., Kim B.C., Brady J.N., Jeang K.T., Kim S.J.: Human T-celllymphotropic virus type 1 tax inhibits transforming growth factor-βsignaling by blocking the association of Smad proteins with Smadbindingelement. J. Biol. Chem., 2002; 277: 33766-33775
  Google Scholar
• 34. Lee K.Y., Bae S.C.: TGF-β-dependent cell growth arrest and apoptosis.J. Biochem. Mol. Biol., 2002; 35: 47-53
  Google Scholar
• 35. Lin H.K., Bergmann S., Pandolfi P.P.: Cytoplasmic PML functionin TGF-β signalling. Nature, 2004; 431: 205-211
  Google Scholar
• 36. Liu F., Hata A., Baker J.C., Doody J., Cárcamo J., Harland R.M.,Massagué J.: A human Mad protein acting as a BMP-regulated transcriptionalactivator. Nature, 1996; 381: 620-623
  Google Scholar
• 37. Liu N.N., Xi Y., Callaghan M.U., Fribley A., Moore-Smith L., ZimmermanJ.W., Pasche B., Zeng Q., Li Y.L.: SMAD4 is a potential prognosticmarker in human breast carcinomas. Tumour Biol., 2014;35: 641-650
  Google Scholar
• 38. Lu L.Y., Chu J.J., Lu P.J., Sung P.K., Hsu C.M., Tseng J.C.: Expressionof intracellular transforming growth factor-beta1 in CD4+CD25+cells in patients with systemic lupus erythematosus. J. Microbiol.Immunol. Infect., 2008; 41: 165-173
  Google Scholar
• 39. Luedecking E.K., DeKosky S.T., Mehdi H., Ganguli M., DeKoskyS.T., Kamboh M.I.: Analysis of genetic polymorphisms in the transforminggrowth factor beta1 gene and the risk of Alzhaimer’s disease.Hum. Genet., 2000; 106: 565-569
  Google Scholar
• 40. Massagué J.: Receptors for the TGF-β family. Cell, 1992; 69: 1067-1070
  Google Scholar
• 41. Massagué J., Seoane J., Wotton D.: Smad transcription factors.Genes Dev., 2005; 19: 2783-2810
  Google Scholar
• 42. Møller G.M., Frost V., Melo J.V., Chantry A.: Upregulation of theTGFβ signalling pathway by Bcr-Abl: implications for haemopoieticcell growth and chronic myeloid leukaemia. FEBS Lett., 2007;581: 1329-1334
  Google Scholar
• 43. Mori N., Morishita M., Tsukazaki T., Giam C.Z., Kumatori A.,Tanaka Y., Yamamoto N.: Human T-cell leukemia virus type I oncoproteinTax represses Smad-dependent transforming growth factorβ signaling through interaction with CREB-binding protein/p300.Blood, 2001; 97: 2137-2144
  Google Scholar
• 44. Moustakas A., Souchelnytskyi S., Heldin C.H.: Smad regulationin TGF-β signal transduction. J. Cell Sci., 2001; 114: 4359-4369
  Google Scholar
• 45. Munoz O., Fend F., de Beaumont R., Husson H., Astier A.,Freedman A.S.: TGFβ-mediated activation of Smad1 in B-cell nonHodgkin›slymphoma and effect on cell proliferation. Leukemia,2004; 18: 2015-2025
  Google Scholar
• 46. Niemczyk M., Foroncewicz B., Mucha K.: Rola TGF beta. Pol.Arch. Med. Wewn., 2005; 113: 401-408
  Google Scholar
• 47. Ogawa S., Kurokawa M., Tanaka T., Tanaka K., Hangaishi A., MitaniK., Kamada N., Yazaki Y., Hirai H.: Increased Evi-1 expression isfrequently observed in blastic crisis of chronic myelocytic leukemia.Leukemia, 1996; 10: 788-794
  Google Scholar
• 48. Osman A., Niles E.G., LoVerde P.T.: Expression of functional Schistosomamansoni Smad 4: role in Erk-mediated transforming growthgrowth factor β (TGF-β) down-regulation. J. Biol. Chem., 2004; 279:6474-6486
  Google Scholar
• 49. Rai D., Kim S.W., McKeller M.R., Dahia P.L., Aguiar R.C.: Targetingof SMAD5 links microRNA-155 to the TGF-β pathway and lymphomagenesis.Proc. Natl. Acad. Sci. USA, 2010; 107: 3111-3116
  Google Scholar
• 50. Roberts A.B., Sporn M.B., Assoian R.K., Smith J.M., Roche N.S.,Wakefield L.M., Heine U.I., Liotta L.A., Falanga V., Kehrl J.H., FauciA.S.: Transforming growth factor type β: rapid induction of fibrosisand angiogenesis in vivo and stimulation of collagen formation invitro. Proc. Natl. Acad. Sci. USA, 1986; 83: 4167-4171
  Google Scholar
• 51. Schutte M., Hruban R.H., Hedrick L., Cho K.R., Nadasdy G.M.,Weinstein C.L., Bova G.S., Isaacs W.B., Cairns P., Nawroz H., SidranskyD., Casero R.A. Jr., Meltzer P.S., Hahn S.A., Kern S.E.: DPC4 genein various tumor types. Cancer Res., 1996; 56: 2527-2530
  Google Scholar
• 52. Shi Y., Massagué J.: Mechanisms of TGF-β signaling from cellmembrane to the nucleus. Cell, 2003; 113: 685-700
  Google Scholar
• 53. Shinto O., Yashiro M., Toyokawa T., Nishii T., Kaizaki R., MatsuzakiT., Noda S., Kubo N., Tanaka H., Doi Y., Ohira M., Muguruma K.,Sawada T., Hirakawa K.: Phosphorylated smad2 in advanced stagegastric carcinoma. BMC Cancer, 2010; 10: 652
  Google Scholar
• 54. Smirne C., Camandona M., Alabiso O., Bellone G., Emanuelli G.:High serum levels of transforming growth factor-beta1, interleukin-10and vascular endothelial growth factor in pancreatic adenocarcinomapatients. Minerva Gastroenterol. Dietol., 1999; 45: 21-27
  Google Scholar
• 55. Takagi Y., Kohmura H., Futamura M., Kida H., Tanemura H., ShimokawaK., Saji S.: Somatic alterations of the DPC4 gene in humancolorectal cancers in vivo. Gastroenterology, 1996; 111: 1369-1372
  Google Scholar
• 56. Talar B., Czyż M.: Rola szlaków sygnałowych TGF-β w nowotworach.Postępy Hig. Med. Dośw., 2013; 67: 1008-1017
  Google Scholar
• 57. Tian M., Neil J.R., Schiemann W.P.: Transforming growth factor-βand the hallmarks of cancer. Cell. Signal., 2011; 23: 951-962
  Google Scholar
• 58. Vázquez P.F., Carlini M.J., Daroqui M.C., Colombo L., DalurzoM.L., Smith D.E., Grasselli J., Pallotta M.G., Ehrlich M., Bal de KierJoffé E.D., Puricelli L.: TGF-beta specifically enhances the metastaticattributes of murine lung adenocarcinoma: implications for humannon-small cell lung cancer. Clin. Exp. Metastasis, 2013; 30: 993-1007
  Google Scholar
• 59. Wolfraim L.A., Fernandez T.M., Mamura M., Fuller W.L., KumarR., Cole D.E., Byfield S., Felici A., Flanders K.C., Walz T.M., RobertsA.B., Aplan P.D., Balis F.M., Letterio J.J.: Loss of Smad3 in acute T-celllymphoblastic leukemia. N. Engl. J. Med., 2004; 351: 552-559
  Google Scholar
• 60. Xie W., Mertens J.C., Reiss D.J., Rimm D.L., Camp R.L., Haffty B.G.,Reiss M.: Alterations of Smad signaling in human breast carcinomaare associated with poor outcome: a tissue microarray study. CancerRes., 2002; 62: 497-505
  Google Scholar
• 61. Xie W., Rimm D.L., Lin Y., Shih W.J., Reiss M.: Loss of Smad signalingin human colorectal cancer is associated with advanced diseaseand poor prognosis. Cancer J., 2003; 9: 302-312
  Google Scholar
• 62. Yamamura Y., Hua X., Bergelson S., Lodish H.F.: Critical roleof Smads and AP-1 complex in transforming growth factor-β-dependent apoptosis. J. Biol. Chem., 2000; 275: 36295-36302
  Google Scholar
• 63. Yang Y.A., Zhang G.M., Feigenbaum L., Zhang Y.E.: Smad3 reducessusceptibility to hepatocarcinoma by sensitizing hepatocytesto apoptosis through downregulation of Bcl-2. Cancer Cell, 2006;9: 445-457
  Google Scholar
• 64. Yeh K.T., Chen T.H., Yang H.W., Chou J.L., Chen L.Y., Yeh C.M.,Chen Y.H., Lin R.I., Su H.Y., Chen G.C., Deatherage D.E., Huang Y.W.,Yan P.S., Lin H.J., Nephew K.P., Huang T.H., Lai H.C., Chan M.W.: AberrantTGFβ/SMAD4 signaling contributes to epigenetic silencingof a putative tumor suppressor, RunX1T1 in ovarian cancer. Epigenetics,2011; 6: 727-739
  Google Scholar
• 65. Yu S.L., Lee D.C., Son J.W., Park C.G., Lee H.Y., Kang J.: Histonedeacetylase 4 mediates SMAD family member 4 deacetylation andinduces 5-fluorouracil resistance in breast cancer cells. Oncol. Rep.,2013; 30: 1293-1300
  Google Scholar
• 66. Zhang L., Sato E., Amagasaki K., Nakao A., Naganuma H.: Participationof an abnormality in the transforming growth factor-βsignaling pathway in resistance of malignant glioma cells to growthinhibition induced by that factor. J. Neurosurg., 2006; 105: 119-128
  Google Scholar

Full text