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Published online 10 July 2006. doi:10.1083/jcb.200512110
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 2, 175-183
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 Transforming growth factor-ß employs HMGA2 to elicit epithelial–mesenchymal transition

Sylvie Thuault1, Ulrich Valcourt2, Maj Petersen3, Guidalberto Manfioletti4, Carl-Henrik Heldin1, and Aristidis Moustakas1

1 Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden
2 Institut National de la Santé et de la Recherche Médicale, Hôpital E. Herriot, 69437 Lyon Cedex 03, France
3 Department of Molecular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, Netherlands
4 Department of Biochemistry, Biophysics, and Macromolecular Chemistry, University of Trieste, 34127 Trieste, Italy

Correspondence to Aristidis Moustakas: aris.moustakas{at}licr.uu.se

Epithelial–mesenchymal transition (EMT) occurs during embryogenesis, carcinoma invasiveness, and metastasis and can be elicited by transforming growth factor-ß (TGF-ß) 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-ß, 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-ß 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.

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.


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