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 β-catenin, partially suppressed Wnt-dependent transcription, and stimulated degradation of both wild-type and “stabilized” forms of β-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 β-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 β-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 β-catenin signaling were modest, these data argue that at pharmacological concentrations ES may impinge on Wnt signaling and promote β-catenin degradation.
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5 August 2002
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July 29 2002
Endostatin is a potential inhibitor of Wnt signaling
Jun-ichi Hanai,
Jun-ichi Hanai
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
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Joachim Gloy,
Joachim Gloy
2Molecular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
3Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02215
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S. Ananth Karumanchi,
S. Ananth Karumanchi
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
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Sujata Kale,
Sujata Kale
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
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Jian Tang,
Jian Tang
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
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Guang Hu,
Guang Hu
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
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Barden Chan,
Barden Chan
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
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Ramani Ramchandran,
Ramani Ramchandran
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
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Vivek Jha,
Vivek Jha
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
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Vikas P. Sukhatme,
Vikas P. Sukhatme
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
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Sergei Sokol
Sergei Sokol
2Molecular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
3Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02215
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Jun-ichi Hanai
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
Joachim Gloy
2Molecular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
3Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02215
S. Ananth Karumanchi
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
Sujata Kale
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
Jian Tang
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
Guang Hu
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
Barden Chan
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
Ramani Ramchandran
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
Vivek Jha
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
Vikas P. Sukhatme
1Department of Medicine and Center for Study of the Tumor Microenvironment, Divisions of Nephrology, Hematology-Oncology
Sergei Sokol
2Molecular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
3Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02215
Address correspondence to Vikas P. Sukhatme, 330 Brookline Ave., Dana 517, Beth Israel Deaconess Medical Center, Boston, MA 02215. Tel.: (617) 667-2105. Fax: (617) 667-7843. E-mail: [email protected]
V.P. Sukhatme, S. Sokol, J. Gloy, and S.A. Karumanchi contributed equally to this work.
*
Abbreviations used in this paper: APC, adenomatous polyposis coli; bFGF, basic FGF; CPAE, calf pulmonary artery endothelial; Dsh, Dishevelled; ES, endostatin; Frz, frizzled; GSK, glycogen synthase kinase; HUVECs, human umbilical vein endothelial cells; TCF, T cell–specific factor; TVP, TCF-VP16.
Received:
March 13 2002
Revision Received:
June 12 2002
Accepted:
June 12 2002
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2002
J Cell Biol (2002) 158 (3): 529–539.
Article history
Received:
March 13 2002
Revision Received:
June 12 2002
Accepted:
June 12 2002
Citation
Jun-ichi Hanai, Joachim Gloy, S. Ananth Karumanchi, Sujata Kale, Jian Tang, Guang Hu, Barden Chan, Ramani Ramchandran, Vivek Jha, Vikas P. Sukhatme, Sergei Sokol; Endostatin is a potential inhibitor of Wnt signaling . J Cell Biol 5 August 2002; 158 (3): 529–539. doi: https://doi.org/10.1083/jcb.200203064
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