Characterization of murine S-endoglin isoform and its effects on tumor development

Abstract

12 páginas, 6 figuras, 2 tablas -- PAGS nros. 4450-4461Endoglin is a transmembrane glycoprotein that acts as an auxiliary receptor for transforming growth factor- (TGF-) and modulates cellular responses to this pleiotropic cytokine. Endoglin is strongly expressed in endothelial cells, where it appears to exert a crucial role in vascular development and angiogenesis. Two endoglin isoforms (L and S), differing in their cytoplasmic domains, have been previously characterized in human tissues. We now demonstrate the existence of similar L- and S-endoglin variants in murine tissues with 47 and 35 amino acids, respectively, in their cytoplasmic tail. RT–PCR analysis showed that L is the predominant endoglin isoform expressed in mouse tissues, although S-endoglin mRNA is significantly expressed in liver and lung, as well as in endothelial cell lines. Furthermore, a protein of size equivalent to recombinant S-endoglin expressed in mammalian cells was detected in mouse endothelial cells by Western blot analysis. L- and S-endoglin isoforms can form disulfide-linked heterodimers, as demonstrated by cotransfection of L- and S-endoglin constructs. To address the role of S-endoglin in vivo, an S-Eng+ transgenic mouse model that targets S-endoglin expression to the endothelium was generated. The lethal phenotype of endoglin-null (Eng-/-) mice was not rescued by breeding S-Eng+ transgenic mice into the endoglin-null background. S-Eng+ mice exhibited reduced tumor growth and neovascularization after transplantation of Lewis lung carcinoma cells. In addition, S-Eng+ mice showed a drastic inhibition of benign papilloma formation when subjected to two-stage chemical skin carcinogenesis. These results point to S-endoglin as an antiangiogenic molecule, in contrast to L-endoglin which is proangiogenicWe thank Sebastián Aliño, Benilde Jiménez and Amparo Cano for their generous gifts of cell lines. We also thank Annette Düwell for helping with mouse breeding and genotyping, and Cristina González for skilful technical assistance. This work was supported by grants from 'Ministerio de Educación y Ciencia (SAF2004-04902 to MQ, SAF2004-01390 to CB and BFU2004-00285-BFI to JML-N), 'Fondo de Investigación Sanitaria' (ISCIII, Red de Centros de Cáncer RTICCC (C03/10) to MQ and PI020200 to CB). EP-G was the recipient of a predoctoral fellowship from the 'Communidad Autónoma de Madrid"Peer reviewe