Gene Expression Signatures of TGF-β/Smad-Induced Responses

  • Erwin P. Böttinger
  • Wenjun Ju
Part of the Proteins and Cell Regulation book series (PROR, volume 5)


Microarray technology has enabled large-scale discovery of transcriptional targets of important signaling pathways, including signal transducers of the TGF-β/Smad family. Thus, numerous studies present gene expression profiles obtained by microarray approaches from a range of normal and malignant cell types exposed to TGF-β, BMP7, BMP2, and other TGF-β family proteins. Here we evaluate newly synthesized TGF-β/Smad gene expression signatures identified by systematic cross-referencing and functional annotation of published lists of TGF-β/Smad target genes. This work provides a valuable compendium for context-dependent analysis of transcriptional profiles of TGF-β/Smad signaling


development gene regulation genomics Microarray mRNA pathogenesis TGF-β transcription signal transduction 


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  1. Balint, E., Lapointe, D., Drissi, H., van der Meijden, C., Young, D.W., Van Wijnen, A.J., Stein, J.L., Stein, G.S., and Lian, J.B., 2003. Phenotype discovery by gene expression profiling: mapping of biological processes linked to BMP-2-mediated osteoblast differentiation. J Cell Biochem 89: 401-426.PubMedCrossRefGoogle Scholar
  2. Borczuk, A.C., Kim, H.K., Yegen, H.A., Friedman, R.A., and Powell, C.A., 2005. Lung adenocarcinoma global profiling identifies type II transforming growth factor-β receptor as a repressor of invasiveness. Am J Respir Crit Care Med 172: 729-737.PubMedCrossRefGoogle Scholar
  3. Border, W.A., and Noble, N.A., 1994. Transforming growth factor β in tissue fibrosis. N Engl J Med 331: 1286-1292.PubMedCrossRefGoogle Scholar
  4. Brown, P.O., and Botstein, D., 1999. Exploring the new world of the genome with DNA microarrays. Nat Genet 21: 33-37.PubMedCrossRefGoogle Scholar
  5. Camenisch, T.D., Molin, D.G., Person, A., Runyan, R.B., Gittenberger-de Groot, A.C., McDonald, J.A., and Klewer, S.E., 2002. Temporal and distinct TGFβ ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev Biol 248: 170-181.PubMedCrossRefGoogle Scholar
  6. Chambers, R.C., Leoni, P., Kaminski, N., Laurent, G.J., and Heller, R.A., 2003. Global expression profiling of fibroblast responses to transforming growth factor-β reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching. Am J Pathol 162: 533-546.PubMedGoogle Scholar
  7. Chen, C.R., Kang, Y., and Massagué, J., 2001. Defective repression of c-myc in breast cancer cells: A loss at the core of the transforming growth factor β growth arrest program. Proc Natl Acad Sci U S A 98: 992-999.PubMedCrossRefGoogle Scholar
  8. Cui, W., Fowlis, D.J., Bryson, S., Duffie, E., Ireland, H., Balmain, A., and Akhurst, R.J., 1996. TGFβ inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86: 531-542.PubMedCrossRefGoogle Scholar
  9. de Jong, D.S., Steegenga, W.T., Hendriks, J.M., van Zoelen, E.J., Olijve, W., and Dechering, K.J., 2004. Regulation of Notch signaling genes during BMP2-induced differentiation of osteoblast precursor cells. Biochem Biophys Res Commun 320: 100-107.PubMedCrossRefGoogle Scholar
  10. de Jong, D.S., van Zoelen, E.J., Bauerschmidt, S., Olijve, W., and Steegenga, W.T., 2002. Microarray analysis of bone morphogenetic protein, transforming growth factor β, and activin early response genes during osteoblastic cell differentiation. J Bone Miner Res 17: 2119-2129.PubMedCrossRefGoogle Scholar
  11. Deacu, E., Mori, Y., Sato, F., Yin, J., Olaru, A., Sterian, A., Xu, Y., Wang, S., Schulmann, K., Berki, A., Kan, T., Abraham, J.M., and Meltzer, S.J., 2004. Activin type II receptor restoration in ACVR2-deficient colon cancer cells induces transforming growth factor-β response pathway genes. Cancer Res 64:, 7690-7696.PubMedCrossRefGoogle Scholar
  12. Derynck, R., Akhurst, R.J., and Balmain, A., 2001. TGF-β signaling in tumor suppression and cancer progression. Nat Genet 29: 117-129.PubMedCrossRefGoogle Scholar
  13. Derynck, R. and Zhang, Y.E., 2003. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425: 577-584.PubMedCrossRefGoogle Scholar
  14. Ellenrieder, V., Hendler, S.F., Boeck, W., Seufferlein, T., Menke, A., Ruhland, C., Adler, G., and Gress, T.M., 2001. Transforming growth factor β treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res 61: 4222-4228.PubMedGoogle Scholar
  15. Ge, G., Seo, N.S., Liang, X., Hopkins, D.R., Hook, M., and Greenspan, D.S., 2004. Bone morphogenetic protein-1/tolloid-related metalloproteinases process osteoglycin and enhance its ability to regulate collagen fibrillogenesis. J Biol Chem 279: 41626-41633.PubMedCrossRefGoogle Scholar
  16. Hartsough, M.T. and Mulder, K.M., 1995. Transforming growth factor β activation of p44mapk in proliferating cultures of epithelial cells. J Biol Chem 270: 7117-7124.PubMedCrossRefGoogle Scholar
  17. Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y.Y., Grinnell, B.W., Richardson, M.A., Topper, J.N., Gimbrone, M.A., Jr., Wrana, J.L., and Falb, D., 1997. The MAD-related protein Smad7 associates with the TGFβ receptor and functions as an antagonist of TGFβ signaling. Cell 89: 1165-1173.PubMedCrossRefGoogle Scholar
  18. Hecht, J.T., Hayes, E., Haynes, R., and Cole, W.G., 2005. COMP mutations, chondrocyte function and cartilage matrix. Matrix Biol 23: 525-533.PubMedCrossRefGoogle Scholar
  19. Hu, G., Jain, K., and Hurle, M., 2005. Revealing transforming growth factor-β signaling transduction in human kidney by gene expression data mining. OMICS 9: 266-280.PubMedCrossRefGoogle Scholar
  20. Ijichi, H., Otsuka, M., Tateishi, K., Ikenoue, T., Kawakami, T., Kanai, F., Arakawa, Y., Seki, N., Shimizu, K., Miyazono, K., Kawabe, T., and Omata, M., 2004. Smad4-independent regulation of p21/WAF1 by transforming growth factor-β. Oncogene 23: 1043-1051.PubMedCrossRefGoogle Scholar
  21. Jazag, A., Ijichi, H., Kanai, F., Imamura, T., Guleng, B., Ohta, M., Imamura, J., Tanaka, Y., Tateishi, K., Ikenoue, T., Kawakami, T., Arakawa, Y., Miyagishi, M., Taira, K., Kawabe, T., and Omata, M., 2005. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference and gene expression profiles induced by transforming growth factor-β. Oncogene 24: 662-671.PubMedCrossRefGoogle Scholar
  22. Kahai, S., Vary, C.P., Gao, Y., and Seth, A., 2004. Collagen, type V, alpha1 (COL5A1) is regulated by TGF-β in osteoblasts. Matrix Biol 23: 445-455.PubMedCrossRefGoogle Scholar
  23. Kang, Y., He, W., Tulley, S., Gupta, G.P., Serganova, I., Chen, C.R., Manova-Todorova, K., Blasberg, R., Gerald, W.L., and Massagué, J., 2005. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway Proc Natl Acad Sci U S A 102: 13909-13914.PubMedCrossRefGoogle Scholar
  24. Kang, Y., Siegel, P.M., Shu, W., Drobnjak, M., Kakonen, S.M., Cordon-Cardo, C., Guise, T.A., and Massagué, J., 2003. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3: 537-549.PubMedCrossRefGoogle Scholar
  25. Karlsson, G., Liu, Y., Larsson, J., Goumans, M.J., Lee, J.S., Thorgeirsson, S.S., Ringner, M., and Karlsson, S., 2005. Gene expression profiling demonstrates that TGF-β signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-β signaling. Physiol Genomics 21: 396-403.PubMedCrossRefGoogle Scholar
  26. Kloeker, S., Major, M.B., Calderwood, D.A., Ginsberg, M.H., Jones, D.A., and Beckerle, M.C., 2004. The Kindler syndrome protein is regulated by transforming growth factor-β and involved in integrin-mediated adhesion. J Biol Chem 279: 6824-6833.PubMedCrossRefGoogle Scholar
  27. Korchynskyi, O., Dechering, K.J., Sijbers, A.M., Olijve, W., and Ten Dijke, P., 2003. Gene array analysis of bone morphogenetic protein type I receptor-induced osteoblast differentiation. J Bone Miner Res 18: 1177-1185.PubMedCrossRefGoogle Scholar
  28. Kowanetz, M., Valcourt, U., Bergström, R., Heldin, C.-H., and Moustakas, A., 2004. Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor β and bone morphogenetic protein. Mol Cell Biol 24: 4241-4254.PubMedCrossRefGoogle Scholar
  29. LaGamba, D., Nawshad, A., and Hay, E.D., 2005. Microarray analysis of gene expression during epithelial-mesenchymal transformation. Dev Dyn 234: 132-142.PubMedCrossRefGoogle Scholar
  30. Levy, L. and Hill, C.S., 2005. Smad4 dependency defines two classes of transforming growth factor β (TGF-β) target genes and distinguishes TGF-β-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol Cell Biol 25: 8108-8125.PubMedCrossRefGoogle Scholar
  31. Li, Y., Zhang, H., Xie, M., Hu, M., Ge, S., Yang, D., Wan, Y., and Yan, B., 2002. Abundant expression of Dec1/stra13/sharp2 in colon carcinoma: its antagonizing role in serum deprivation-induced apoptosis and selective inhibition of procaspase activation. Biochem. J 367: 413-422.PubMedCrossRefGoogle Scholar
  32. Lockhart, D.J., Dong, H., Byrne, M.C., Follettie, M.T., Gallo, M.V., Chee, M.S., Mittmann, M., Wang, C., Kobayashi, M., Horton, H., and Brown, E.L., 1996. Expression monitoring by hybridization to high-density oligonucleotide arrays [see comments]. Nat Biotechnol 14: 1675-1680.PubMedCrossRefGoogle Scholar
  33. Lockhart, D.J. and Winzeler, E.A., 2000. Genomics, gene expression and DNA arrays. Nature 405: 827-836.PubMedCrossRefGoogle Scholar
  34. Lucchini, M., Romeas, A., Couble, M.L., Bleicher, F., Magloire, H., and Farges, J.C., 2002. TGF β signaling and stimulation of osteoadherin in human odontoblasts in vitro. Connect Tissue Res 43: 345-353.PubMedGoogle Scholar
  35. Luo, X., Ding, L., Xu, J., and Chegini, N., 2005. Gene expression profiling of leiomyoma and myometrial smooth muscle cells in response to transforming growth factor-β. Endocrinology 146: 1097-1118.PubMedCrossRefGoogle Scholar
  36. Massagué, J., 2004. G1 cell-cycle control and cancer. Nature 432: 298-306.PubMedCrossRefGoogle Scholar
  37. Matsuyama, S., Iwadate, M., Kondo, M., Saitoh, M., Hanyu, A.,Shimizu, K., Aburatani, H., Mishima, H.K., Imamura, T., Miyazono, K., and Miyazawa, K., 2003. SB-431542 and Gleevec inhibit transforming growth factor-β-induced proliferation of human osteosarcoma cells. Cancer Res 63: 7791-7798.PubMedGoogle Scholar
  38. Minn, A.J., Gupta, G.P., Siegel, P.M., Bos, P.D., Shu, W., Giri, D.D., Viale, A., Olshen, A.B., Gerald, W.L., and Massagué, J., 2005a. Genes that mediate breast cancer metastasis to lung. Nature 436: 518-524.CrossRefGoogle Scholar
  39. Minn, A.J., Kang, Y., Serganova, I., Gupta, G.P., Giri, D.D., Doubrovin, M., Ponomarev, V., Gerald, W.L., Blasberg, R., and Massagué, J., 2005b. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115: 44-55.CrossRefGoogle Scholar
  40. Miyazaki, K., Kawamoto, T., Tanimoto, K., Nishiyama, M., Honda, H., and Kato, Y., 2002. Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes. J Biol Chem 277: 47014-47021.PubMedCrossRefGoogle Scholar
  41. Miyazono, K., Maeda, S., and Imamura, T., 2005. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16: 251-263.PubMedCrossRefGoogle Scholar
  42. Miyazono, K., ten Dijke, P., and Heldin, C.-H., 2000. TGF-β signaling by Smad proteins. Adv Immunol 75: 115-157.PubMedCrossRefGoogle Scholar
  43. Nakao, A., Afrakhte, M., Morén, A., Nakayama, T., Christian, J.L., Heuchel, R., Kawabata, M., Heldin, N.-E., Heldin, C.-H., and ten Dijke, P., 1997. Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling [see comments]. Nature 389: 631-635.PubMedCrossRefGoogle Scholar
  44. Oh, S.P., Seki, T., Goss, K.A., Imamura, T., Yi, Y., Donahoe, P.K., Li, L., Miyazono, K., ten Dijke, P., Kim, S., and Li, E., 2000. Activin receptor-like kinase 1 modulates transforming growth factor-β signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A 97: 2626-2631.PubMedCrossRefGoogle Scholar
  45. Ota, T., Fujii, M., Sugizaki, T., Ishii, M., Miyazawa, K., Aburatani, H., and Miyazono, K., 2002. Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-β in human umbilical vein endothelial cells. J Cell Physiol 193: 299-318.PubMedCrossRefGoogle Scholar
  46. Peng, Y., Kang, Q., Cheng, H., Li, X., Sun, M.H., Jiang, W., Luu, H.H., Park, J.Y., Haydon, R.C., and He, T.C., 2003. Transcriptional characterization of bone morphogenetic proteins (BMPs)-mediated osteogenic signaling. J Cell Biochem 90: 1149-1165.PubMedCrossRefGoogle Scholar
  47. Perbal, B., 2004. CCN proteins: multifunctional signalling regulators. Lancet 363: 62-64.PubMedCrossRefGoogle Scholar
  48. Perry, S.V., 2001. Vertebrate tropomyosin: distribution, properties and function. J Muscle Res Cell Motil 22: 5-49.PubMedCrossRefGoogle Scholar
  49. Proetzel, G., Pawlowski, S.A., Wiles, M.V., Yin, M., Boivin, G.P., Howles, P.N., Ding, J., Ferguson, M.W.J., and Doetschman, T., 1995. Transforming growth factor-b3 is required for secondary palate fusion. Nature Genet 11: 409-414.PubMedCrossRefGoogle Scholar
  50. Renzoni, E.A., Abraham, D.J., Howat, S., Shi-Wen, X., Sestini, P., Bou-Gharios, G., Wells, A.U., Veeraraghavan, S., Nicholson, A.G., Denton, C.P., Leask, A., Pearson, J.D., Black, C.M., Welsh, K.I., and du Bois, R.M., 2004. Gene expression profiling reveals novel TGFβ targets in adult lung fibroblasts. Respir Res 5: 24.PubMedCrossRefGoogle Scholar
  51. Ruzek, M.C., Hawes, M., Pratt, B., McPherson, J., Ledbetter, S., Richards, S.M., and Garman, R.D., 2003. Minimal effects on immune parameters following chronic anti-TGF-β monoclonal antibody administration to normal mice. Immunopharmacol. Immunotoxicol 25: 235-257.CrossRefGoogle Scholar
  52. Schena, M., Shalon, D., Davis, R.W., and Brown, P.O., 1995. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270: 467-470.PubMedCrossRefGoogle Scholar
  53. Schnaper, H.W. and Kopp, J.B., 2003. Renal fibrosis. Front Biosci 8: e68-e86.PubMedGoogle Scholar
  54. Shen, M., Yoshida, E., Yan, W., Kawamoto, T., Suardita, K., Koyano, Y., Fujimoto, K., Noshiro, M., and Kato, Y., 2002. Basic helix-loop-helix protein DEC1 promotes chondrocyte differentiation at the early and terminal stages. J Biol Chem 277: 50112-50120.PubMedCrossRefGoogle Scholar
  55. Stock, M., Schafer, H., Fliegauf, M., and Otto, F., 2004. Identification of novel genes of the bone-specific transcription factor Runx2. J Bone Miner Res 19: 959-972.PubMedCrossRefGoogle Scholar
  56. Untergasser, G., Gander, R., Lilg, C., Lepperdinger, G., Plas, E., and Berger, P., 2005. Profiling molecular targets of TGF-β in prostate fibroblast-to-myofibroblast transdifferentiation. Mech Ageing Dev 126: 59-69.PubMedCrossRefGoogle Scholar
  57. Vaes, B.L., Dechering, K.J., Feijen, A., Hendriks, J.M., Lefevre, C., Mummery, C.L., Olijve, W., van Zoelen, E.J., and Steegenga, W.T., 2002. Comprehensive microarray analysis of bone morphogenetic protein 2-induced osteoblast differentiation resulting in the identification of novel markers for bone development. J Bone Miner Res 17: 2106-2118.PubMedCrossRefGoogle Scholar
  58. Valcourt, U., Kowanetz, M., Niimi, H., Heldin, C.-H., and Moustakas, A., 2005. TGF-β and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell 16: 1987-2002.PubMedCrossRefGoogle Scholar
  59. Varga, A.E., Stourman, N.V., Zheng, Q., Safina, A.F., Quan, L., Li, X., Sossey-Alaoui, K., and Bakin, A.V., 2005. Silencing of the Tropomyosin-1 gene by DNA methylation alters tumor suppressor function of TGF-β. Oncogene 24: 5043-5052.PubMedCrossRefGoogle Scholar
  60. van ’t Veer, L.J., Dai, H., van de Vijver, M.J., He, Y.D., Hart, A.A., Mao, M., Peterse, H.L., van der, K.K., Marton, M.J., Witteveen, A.T., Schreiber, G.J., Kerkhoven, R.M., Roberts, C., Linsley, P.S., Bernards, R., and Friend, S.H., 2002. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415: 530-536.PubMedCrossRefGoogle Scholar
  61. Verrecchia, F., Chu, M.L., and Mauviel, A., 2001. Identification of novel TGF-β/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem 276: 17058-17062.PubMedCrossRefGoogle Scholar
  62. Wakefield, L.M. and Roberts, A.B., 2002. TGF-β signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 12: 22-29.PubMedCrossRefGoogle Scholar
  63. Wu, K., Yang, Y., Wang, C., Davoli, M.A., D’Amico, M., Li, A., Cveklova, K., Kozmik, Z., Lisanti, M.P., Russell, R.G., Cvekl, A., and Pestell, R.G., 2003. DACH1 inhibits transforming growth factor-β signaling through binding Smad4. J Biol Chem 278: 51673-51684.PubMedCrossRefGoogle Scholar
  64. Xie, L., Law, B.K., Aakre, M.E., Edgerton, M., Shyr, Y., Bhowmick, N.A., and Moses, H.L., 2003. Transforming growth factor β-regulated gene expression in a mouse mammary gland epithelial cell line. Breast Cancer Res 5: R187-R198.PubMedCrossRefGoogle Scholar
  65. Xie, L., Law, B.K., Chytil, A.M., Brown, K.A., Aakre, M.E., and Moses, H.L., 2004. Activation of the Erk pathway is required for TGF-β-induced EMT in vitro. Neoplasia 6: 603-610.PubMedCrossRefGoogle Scholar
  66. Yang, Y.A., Dukhanina, O., Tang, B., Mamura, M., Letterio, J.J., MacGregor, J., Patel, S.C., Khozin, S., Liu, Z.Y., Green, J., Anver, M.R., Merlino, G., and Wakefield, L.M., 2002. Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects. J Clin Invest 109: 1607-1615.PubMedCrossRefGoogle Scholar
  67. Yang, Y.C., Piek, E., Zavadil, J., Liang, D., Xie, D., Heyer, J., Pavlidis, P., Kucherlapati, R., Roberts, A.B., and Böttinger, E.P., 2003. Hierarchical model of gene regulation by transforming growth factor β Proc Natl Acad Sci U S A 100: 10269-10274.PubMedCrossRefGoogle Scholar
  68. Yingling, J.M., Blanchard, K.L., and Sawyer, J.S., 2004. Development of TGF-β signalling inhibitors for cancer therapy. Nat Rev Drug Discov 3: 1011-1022.PubMedCrossRefGoogle Scholar
  69. Zavadil, J., Bitzer, M., Liang, D., Yang, Y.C., Massimi, A., Kneitz, S., Piek, E., and Böttinger, E.P., 2001. Genetic programs of epithelial cell plasticity directed by transforming growth factor-β. Proc Natl Acad Sci U S A 98: 6686-6691.PubMedCrossRefGoogle Scholar
  70. Zavadil, J. and Böttinger, E.P., 2005. TGF-β and epithelial-to-mesenchymal transitions. Oncogene 24: 5764-5774.PubMedCrossRefGoogle Scholar
  71. Zavadil, J., Cermak, L., Soto-Nieves, N., and Böttinger, E.P., 2004. Integration of TGF-β/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 23: 1155-1165.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • Erwin P. Böttinger
    • 1
  • Wenjun Ju
    • 1
  1. 1.Mount Sinai School of MedicineNew York CityUSA

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