title: The TGF-beta co-receptor endoglin modulates the expression and transforming potential of H-Ras.
abstract: Endoglin 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.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Santibanez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pérez-Gómez
authors.forename: Africa
authors.initials: A
authors.lastname: Fernandez-L
authors.forename: Eva M
authors.initials: EM
authors.lastname: Garrido-Martin
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.forename: Calvin P H
authors.initials: CP
authors.lastname: Vary
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintanilla
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabéu
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D000071063:Endoglin; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D015603:Keratinocytes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D051785:Smad Proteins / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse