Endostatin is a potential inhibitor of Wnt signaling.
Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. To gain insight into ES-mediated signaling, we studied the effects of ES RNA on Xenopus embryogenesis and observed developmental abnormalities consistent with impaired Wnt signaling. ES RNA blocked the axis duplication induced by beta-catenin, partially suppressed Wnt-dependent transcription, and stimulated degradation of both wild-type and "stabilized" forms of beta-catenin, the latter suggesting that ES signaling does not involve glycogen synthase kinase 3. Moreover, ES uses a pathway independent of the Siah1 protein in targeting beta-catenin for proteasome-mediated degradation. ES failed to suppress the effects of T cell-specific factor (TCF)-VP16 (TVP), a constitutive downstream transcriptional activator that acts independently of beta-catenin. Importantly, these data were replicated in endothelial cells and also in the DLD-1 colon carcinoma cells with the mutated adenomatous polyposis coli protein. Finally, suppression of endothelial cell migration and inhibition of cell cycle by ES were reversed by TVP. Though high levels of ES were used in both the Xenopus and endothelial cell studies and the effects on beta-catenin signaling were modest, these data argue that at pharmacological concentrations ES may impinge on Wnt signaling and promote beta-catenin degradation.
Hanai
Jun-ichi
J
Department of Medicine and Center for Study of the Tumor Microenvironment, Division of Nephrology, Hematology-Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Gloy
Joachim
J
Karumanchi
S Ananth
SA
Kale
Sujata
S
Tang
Jian
J
Hu
Guang
G
Chan
Barden
B
Ramchandran
Ramani
R
Jha
Vivek
V
Sukhatme
Vikas P
VP
Sokol
Sergei
S
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D043170:Collagen Type XVIII; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006133:Growth Substances / Q000494:pharmacology; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000002:abnormalities* / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins; D051176:beta Catenin; D000098563:Seven in Absentia Proteins
D020533:Angiogenesis Inhibitors; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; D043170:Collagen Type XVIII; D003598:Cytoskeletal Proteins; D043169:Endostatins; D006133:Growth Substances; D019812:Heparan Sulfate Proteoglycans; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D003094:Collagen; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins