This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kowanetz, M.
Right arrow Articles by Moustakas, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kowanetz, M.
Right arrow Articles by Moustakas, A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, May 2004, p. 4241-4254, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4241-4254.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Id2 and Id3 Define the Potency of Cell Proliferation and Differentiation Responses to Transforming Growth Factor ß and Bone Morphogenetic Protein{dagger}

Marcin Kowanetz, Ulrich Valcourt, Rosita Bergström,{ddagger} Carl-Henrik Heldin, and Aristidis Moustakas*

Ludwig Institute for Cancer Research, SE-751 24 Uppsala, Sweden

Received 14 October 2003/ Returned for modification 25 November 2003/ Accepted 9 February 2004

Transforming growth factors ß (TGF-ßs) inhibit growth of epithelial cells and induce differentiation changes, such as epithelial-mesenchymal transition (EMT). On the other hand, bone morphogenetic proteins (BMPs) weakly affect epithelial cell growth and do not induce EMT. Smad4 transmits signals from both TGF-ß and BMP pathways. Stimulation of Smad4-deficient epithelial cells with TGF-ß1 or BMP-7 in the absence or presence of exogenous Smad4, followed by cDNA microarray analysis, revealed 173 mostly Smad4-dependent, TGF-ß-, or BMP-responsive genes. Among 25 genes coregulated by both factors, inhibitors of differentiation Id2 and Id3 showed long-term repression by TGF-ß and sustained induction by BMP. The opposing regulation of Id genes is critical for proliferative and differentiation responses. Hence, ectopic Id2 or Id3 expression renders epithelial cells refractory to growth inhibition and EMT induced by TGF-ß, phenocopying the BMP response. Knockdown of endogenous Id2 or Id3 sensitizes epithelial cells to BMP, leading to robust growth inhibition and induction of transdifferentiation. Thus, Id genes sense Smad signals and create a permissive or refractory nuclear environment that defines decisions of cell fate and proliferation.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Box 595 Biomedical Center, SE-751 24 Uppsala, Sweden. Phone: 46-18-160414. Fax: 46-18-160420. E-mail: aris.moustakas{at}licr.uu.se.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Development and Genetics, Evolution Biology Centre, Uppsala University, SE-752 36 Uppsala, Sweden.

Molecular and Cellular Biology, May 2004, p. 4241-4254, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4241-4254.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Moustakas, A., Heldin, C.-H. (2009). The regulation of TGF{beta} signal transduction. Development 136: 3699-3714 [Abstract] [Full Text]  
  • Wells, J., Lee, B., Cai, A. Q., Karapetyan, A., Lee, W.-J., Rugg, E., Sinha, S., Nie, Q., Dai, X. (2009). Ovol2 Suppresses Cell Cycling and Terminal Differentiation of Keratinocytes by Directly Repressing c-Myc and Notch1. J. Biol. Chem. 284: 29125-29135 [Abstract] [Full Text]  
  • Murakami, M., Kawachi, H., Ogawa, K., Nishino, Y., Funaba, M. (2009). Receptor expression modulates the specificity of transforming growth factor-beta signaling pathways.. GENES CELLS 14: 469-482 [Abstract] [Full Text]  
  • Thuault, S., Tan, E-J., Peinado, H., Cano, A., Heldin, C.-H., Moustakas, A. (2008). HMGA2 and Smads Co-regulate SNAIL1 Expression during Induction of Epithelial-to-Mesenchymal Transition. J. Biol. Chem. 283: 33437-33446 [Abstract] [Full Text]  
  • Kowanetz, M., Lonn, P., Vanlandewijck, M., Kowanetz, K., Heldin, C.-H., Moustakas, A. (2008). TGF{beta} induces SIK to negatively regulate type I receptor kinase signaling. JCB 182: 655-662 [Abstract] [Full Text]  
  • Yan, W., Liu, G., Scoumanne, A., Chen, X. (2008). Suppression of Inhibitor of Differentiation 2, a Target of Mutant p53, Is Required for Gain-of-Function Mutations. Cancer Res. 68: 6789-6796 [Abstract] [Full Text]  
  • Lin, L., Zhou, Z., Zheng, L., Alber, S., Watkins, S., Ray, P., Kaminski, N., Zhang, Y., Morse, D. (2008). Cross Talk between Id1 and Its Interactive Protein Dril1 Mediate Fibroblast Responses to Transforming Growth Factor-{beta} in Pulmonary Fibrosis. Am. J. Pathol. 173: 337-346 [Abstract] [Full Text]  
  • Rajagopal, J., Carroll, T. J., Guseh, J. S., Bores, S. A., Blank, L. J., Anderson, W. J., Yu, J., Zhou, Q., McMahon, A. P., Melton, D. A. (2008). Wnt7b stimulates embryonic lung growth by coordinately increasing the replication of epithelium and mesenchyme. Development 135: 1625-1634 [Abstract] [Full Text]  
  • Fritah, A., Saucier, C., De Wever, O., Bracke, M., Bieche, I., Lidereau, R., Gespach, C., Drouot, S., Redeuilh, G., Sabbah, M. (2008). Role of WISP-2/CCN5 in the Maintenance of a Differentiated and Noninvasive Phenotype in Human Breast Cancer Cells. Mol. Cell. Biol. 28: 1114-1123 [Abstract] [Full Text]  
  • Song, Y., Zhao, C., Dong, L., Fu, M., Xue, L., Huang, Z., Tong, T., Zhou, Z., Chen, A., Yang, Z., Lu, N., Zhan, Q. (2008). Overexpression of cyclin B1 in human esophageal squamous cell carcinoma cells induces tumor cell invasive growth and metastasis. Carcinogenesis 29: 307-315 [Abstract] [Full Text]  
  • Pangas, S. A., Li, X., Umans, L., Zwijsen, A., Huylebroeck, D., Gutierrez, C., Wang, D., Martin, J. F., Jamin, S. P., Behringer, R. R., Robertson, E. J., Matzuk, M. M. (2008). Conditional Deletion of Smad1 and Smad5 in Somatic Cells of Male and Female Gonads Leads to Metastatic Tumor Development in Mice. Mol. Cell. Biol. 28: 248-257 [Abstract] [Full Text]  
  • Zhang, H., Lawson, W. E., Polosukhin, V. V., Pozzi, A., Blackwell, T. S., Litingtung, Y., Chiang, C. (2007). Inhibitor of Differentiation 1 Promotes Endothelial Survival in a Bleomycin Model of Lung Injury in Mice. Am. J. Pathol. 171: 1113-1126 [Abstract] [Full Text]  
  • Willis, B. C., Borok, Z. (2007). TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 293: L525-L534 [Abstract] [Full Text]  
  • Shirakihara, T., Saitoh, M., Miyazono, K. (2007). Differential Regulation of Epithelial and Mesenchymal Markers by {delta}EF1 Proteins in Epithelial Mesenchymal Transition Induced by TGF-beta. Mol. Biol. Cell 18: 3533-3544 [Abstract] [Full Text]  
  • Theriault, B. L., Shepherd, T. G., Mujoomdar, M. L., Nachtigal, M. W. (2007). BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells. Carcinogenesis 28: 1153-1162 [Abstract] [Full Text]  
  • Kinoshita, K., Iimuro, Y., Otogawa, K., Saika, S., Inagaki, Y., Nakajima, Y., Kawada, N., Fujimoto, J., Friedman, S. L, Ikeda, K. (2007). Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats. Gut 56: 706-714 [Abstract] [Full Text]  
  • Shiou, S.-R., Singh, A. B., Moorthy, K., Datta, P. K., Washington, M. K., Beauchamp, R. D., Dhawan, P. (2007). Smad4 Regulates Claudin-1 Expression in a Transforming Growth Factor-{beta}-Independent Manner in Colon Cancer Cells. Cancer Res. 67: 1571-1579 [Abstract] [Full Text]  
  • Yoshikawa, M., Hishikawa, K., Marumo, T., Fujita, T. (2007). Inhibition of Histone Deacetylase Activity Suppresses Epithelial-to-Mesenchymal Transition Induced by TGF-beta1 in Human Renal Epithelial Cells. J. Am. Soc. Nephrol. 18: 58-65 [Abstract] [Full Text]  
  • Yoon, B. S., Pogue, R., Ovchinnikov, D. A., Yoshii, I., Mishina, Y., Behringer, R. R., Lyons, K. M. (2006). BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways. Development 133: 4667-4678 [Abstract] [Full Text]  
  • Morrell, N. W. (2006). Pulmonary Hypertension Due to BMPR2 Mutation: A New Paradigm for Tissue Remodeling?. Proc Am Thorac Soc 3: 680-686 [Abstract] [Full Text]  
  • Moreno-Bueno, G., Cubillo, E., Sarrio, D., Peinado, H., Rodriguez-Pinilla, S. M., Villa, S., Bolos, V., Jorda, M., Fabra, A., Portillo, F., Palacios, J., Cano, A. (2006). Genetic Profiling of Epithelial Cells Expressing E-Cadherin Repressors Reveals a Distinct Role for Snail, Slug, and E47 Factors in Epithelial-Mesenchymal Transition. Cancer Res. 66: 9543-9556 [Abstract] [Full Text]  
  • Thuault, S., Valcourt, U., Petersen, M., Manfioletti, G., Heldin, C.-H., Moustakas, A. (2006). Transforming growth factor-{beta} employs HMGA2 to elicit epithelial-mesenchymal transition. JCB 174: 175-183 [Abstract] [Full Text]  
  • Ge, R., Rajeev, V., Ray, P., Lattime, E., Rittling, S., Medicherla, S., Protter, A., Murphy, A., Chakravarty, J., Dugar, S., Schreiner, G., Barnard, N., Reiss, M. (2006). Inhibition of Growth and Metastasis of Mouse Mammary Carcinoma by Selective Inhibitor of Transforming Growth Factor-{beta} Type I Receptor Kinase In vivo.. Clin. Cancer Res. 12: 4315-4330 [Abstract] [Full Text]  
  • Fleisch, M. C, Maxwell, C. A, Barcellos-Hoff, M.-H. (2006). The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs.. Endocr Relat Cancer 13: 379-400 [Abstract] [Full Text]  
  • Hua, H., Zhang, Y.-Q., Dabernat, S., Kritzik, M., Dietz, D., Sterling, L., Sarvetnick, N. (2006). BMP4 Regulates Pancreatic Progenitor Cell Expansion through Id2. J. Biol. Chem. 281: 13574-13580 [Abstract] [Full Text]  
  • Onken, M. D., Ehlers, J. P., Worley, L. A., Makita, J., Yokota, Y., Harbour, J. W. (2006). Functional Gene Expression Analysis Uncovers Phenotypic Switch in Aggressive Uveal Melanomas.. Cancer Res. 66: 4602-4609 [Abstract] [Full Text]  
  • Nair, M., Teng, A., Bilanchone, V., Agrawal, A., Li, B., Dai, X. (2006). Ovol1 regulates the growth arrest of embryonic epidermal progenitor cells and represses c-myc transcription. JCB 173: 253-264 [Abstract] [Full Text]  
  • Saika, S., Ikeda, K., Yamanaka, O., Flanders, K. C., Ohnishi, Y., Nakajima, Y., Muragaki, Y., Ooshima, A. (2006). Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice. Am. J. Physiol. Cell Physiol. 290: C282-C289 [Abstract] [Full Text]  
  • Izumi, N., Mizuguchi, S., Inagaki, Y., Saika, S., Kawada, N., Nakajima, Y., Inoue, K., Suehiro, S., Friedman, S. L., Ikeda, K. (2006). BMP-7 opposes TGF-{beta}1-mediated collagen induction in mouse pulmonary myofibroblasts through Id2. Am. J. Physiol. Lung Cell. Mol. Physiol. 290: L120-L126 [Abstract] [Full Text]  
  • Gao, S., Steffen, J., Laughon, A. (2005). Dpp-responsive Silencers Are Bound by a Trimeric Mad-Medea Complex. J. Biol. Chem. 280: 36158-36164 [Abstract] [Full Text]  
  • Moustakas, A., Heldin, C.-H. (2005). Non-Smad TGF-{beta} signals. J. Cell Sci. 118: 3573-3584 [Abstract] [Full Text]  
  • Moren, A., Imamura, T., Miyazono, K., Heldin, C.-H., Moustakas, A. (2005). Degradation of the Tumor Suppressor Smad4 by WW and HECT Domain Ubiquitin Ligases. J. Biol. Chem. 280: 22115-22123 [Abstract] [Full Text]  
  • Nudi, M., Ouimette, J.-F., Drouin, J. (2005). Bone Morphogenic Protein (Smad)-Mediated Repression of Proopiomelanocortin Transcription by Interference with Pitx/Tpit Activity. Mol. Endocrinol. 19: 1329-1342 [Abstract] [Full Text]  
  • Valcourt, U., Kowanetz, M., Niimi, H., Heldin, C.-H., Moustakas, A. (2005). TGF-{beta} and the Smad Signaling Pathway Support Transcriptomic Reprogramming during Epithelial-Mesenchymal Cell Transition. Mol. Biol. Cell 16: 1987-2002 [Abstract] [Full Text]  
  • Haudenschild, D. R., Palmer, S. M., Moseley, T. A., You, Z., Reddi, A. H. (2004). Bone Morphogenetic Protein (BMP)-6 Signaling and BMP Antagonist Noggin in Prostate Cancer. Cancer Res. 64: 8276-8284 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»