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The TGF-β co-receptor endoglin modulates the expression and transforming potential of H-Ras

AuthorsSantibañez, Juan F.; Pérez-Gómez, Eduardo ; Fernandez-Lopez, Africa ; Garrido-Martin, Eva M. ; Carnero, Amancio ; Malumbres, Marcos; Vary, Calvin P. H.; Quintanilla, Miguel ; Bernabéu, Carmelo
Issue Date30-Sep-2010
PublisherOxford University Press
CitationCarcinogenesis 31(12): 2145-2154 (2010)
AbstractEndoglin is a coreceptor for transforming growth factor-β (TGF-β) that acts as a suppressor of malignancy during mouse skin carcinogenesis. Because in this model system H-Ras activation drives tumor initiation and progression, we have assessed the effects of endoglin on the expression of H-Ras in transformed keratinocytes. We found that TGF-β1 increases the expression of H-Ras at both messenger RNA and protein levels. The TGF-β1-induced H-Ras promoter transactivation was Smad4 independent but mediated by the activation of the TGF-β type I receptor ALK5 and the Ras-mitogen-activated protein kinase (MAPK) pathway. Endoglin attenuated stimulation by TGF-β1 of both MAPK signaling activity and H-Ras gene expression. Moreover, endoglin inhibited the Ras/MAPK pathway in transformed epidermal cells containing an H-Ras oncogene, as evidenced by the levels of Ras-guanosine triphosphate, phospho-MAPK kinase (MEK) and phospho-extracellular signal-regulated kinase (ERK) as well as the expression of c-fos, a MAPK downstream target gene. Interestingly, in spindle carcinoma cells, that have a hyperactivated Ras/MAPK pathway, endoglin inhibited ERK phosphorylation without affecting MEK or Ras activity. The mechanism for this effect is unknown but strongly depends on the endoglin extracellular domain. Because the MAPK pathway is a downstream mediator of the transforming potential of Ras, the effect of endoglin on the oncogenic function of H-Ras was assessed. Endoglin inhibited the transforming capacity of H-Ras(Q61K) and H-Ras(G12V) oncogenes in a NIH3T3 focus formation assay. The ability to interfere with the expression and oncogenic potential of H-Ras provides a new face of the suppressor role exhibited by endoglin in H-Ras-driven carcinogenesis.
Description10 páginas, 6 figuras.-- El pdf del artículo es la versión pre-print.
Publisher version (URL)http://dx.doi.org/ 10.1093/carcin/bgq199
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