Characterization of murine S-endoglin isoform and its effects on tumor development.
Endoglin is a transmembrane glycoprotein that acts as an auxiliary receptor for transforming growth factor-beta (TGF-beta) 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. Oncogene (2005) 24, 4450-4461. doi:10.1038/sj.onc.1208644 Published online 4 April 2005.
Pérez-Gómez
Eduardo
E
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Arturo Duperier 4, 28029 Madrid, Spain.
Eleno
Nélida
N
López-Novoa
Jose Miguel
JM
Ramirez
Jose Ramón
JR
Velasco
Beatriz
B
Letarte
Michelle
M
Bernabéu
Carmelo
C
Quintanilla
Miguel
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D000071063:Endoglin; D005260:Female; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment
D018076:DNA, Complementary; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger