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

Oncogene volume 24, pages 4450–4461 (2005)Cite this article

Abstract

Endoglin is a transmembrane glycoprotein that acts as an auxiliary receptor for transforming growth factor-β (TGF-β) 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 proangiogenic.

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Acknowledgements

We 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’.

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  1. Supplementary information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Arturo Duperier 4, 28029, Madrid, Spain

    Eduardo Pérez-Gómez & Miguel Quintanilla

  2. Departamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007, Salamanca, Spain

    Nélida Eleno & Jose Miguel López-Novoa

  3. Departamento de Anatomía Patológica, Hospital Gomez-Ulla, Glorieta del Ejercito, 28047, Madrid, Spain

    Jose Ramón Ramirez

  4. Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040, Madrid, Spain

    Beatriz Velasco & Carmelo Bernabéu

  5. Cancer Research Program, The Hospital for Sick Children and Department of Immunology, University of Toronto, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8

    Michelle Letarte

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  1. Eduardo Pérez-Gómez
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Pérez-Gómez, E., Eleno, N., López-Novoa, J. et al. Characterization of murine S-endoglin isoform and its effects on tumor development. Oncogene 24, 4450–4461 (2005). https://doi.org/10.1038/sj.onc.1208644

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