Epithelial–mesenchymal transition (EMT) occurs during embryogenesis, carcinoma invasiveness, and metastasis and can be elicited by transforming growth factor-β (TGF-β) signaling via intracellular Smad transducers. The molecular mechanisms that control the onset of EMT remain largely unexplored. Transcriptomic analysis revealed that the high mobility group A2 (HMGA2) gene is induced by the Smad pathway during EMT. Endogenous HMGA2 mediates EMT by TGF-β, whereas ectopic HMGA2 causes irreversible EMT characterized by severe E-cadherin suppression. HMGA2 provides transcriptional input for the expression control of four known regulators of EMT, the zinc-finger proteins Snail and Slug, the basic helix-loop-helix protein Twist, and inhibitor of differentiation 2. We delineate a pathway that links TGF-β signaling to the control of epithelial differentiation via HMGA2 and a cohort of major regulators of tumor invasiveness and metastasis. This network of signaling/transcription factors that work sequentially to establish EMT suggests that combinatorial detection of these proteins could serve as a new tool for EMT analysis in cancer patients.
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17 July 2006
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July 10 2006
Transforming growth factor-β employs HMGA2 to elicit epithelial–mesenchymal transition
Sylvie Thuault,
Sylvie Thuault
1Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden
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Ulrich Valcourt,
Ulrich Valcourt
2Institut National de la Santé et de la Recherche Médicale, Hôpital E. Herriot, 69437 Lyon Cedex 03, France
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Maj Petersen,
Maj Petersen
3Department of Molecular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
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Guidalberto Manfioletti,
Guidalberto Manfioletti
4Department of Biochemistry, Biophysics, and Macromolecular Chemistry, University of Trieste, 34127 Trieste, Italy
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Carl-Henrik Heldin,
Carl-Henrik Heldin
1Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden
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Aristidis Moustakas
Aristidis Moustakas
1Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden
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Sylvie Thuault
1Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden
Ulrich Valcourt
2Institut National de la Santé et de la Recherche Médicale, Hôpital E. Herriot, 69437 Lyon Cedex 03, France
Maj Petersen
3Department of Molecular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
Guidalberto Manfioletti
4Department of Biochemistry, Biophysics, and Macromolecular Chemistry, University of Trieste, 34127 Trieste, Italy
Carl-Henrik Heldin
1Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden
Aristidis Moustakas
1Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden
Correspondence to Aristidis Moustakas: [email protected]
Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; EMT, epithelial–mesenchymal transition; Gapdh, glyceraldehyde-3′-phosphate dehydrogenase; HMG, high mobility group; Id, inhibitor of differentiation; ZO-1, zonula occludens 1.
Received:
December 20 2005
Accepted:
June 14 2006
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2006
J Cell Biol (2006) 174 (2): 175–183.
Article history
Received:
December 20 2005
Accepted:
June 14 2006
Citation
Sylvie Thuault, Ulrich Valcourt, Maj Petersen, Guidalberto Manfioletti, Carl-Henrik Heldin, Aristidis Moustakas; Transforming growth factor-β employs HMGA2 to elicit epithelial–mesenchymal transition . J Cell Biol 17 July 2006; 174 (2): 175–183. doi: https://doi.org/10.1083/jcb.200512110
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