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Am J Physiol Cell Physiol 293: C1404-C1411, 2007. First published August 8, 2007; doi:10.1152/ajpcell.00058.2007
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VASCULAR BIOLOGY

MEKK3 is required for endothelium function but is not essential for tumor growth and angiogenesis

Yong Deng,1,2 Jianhua Yang,2 Marya McCarty,3 and Bing Su1,2

1Department of Immunobiology and Vascular Biology and Transplantation Program, Yale University School of Medicine, New Haven, Connecticut; and Departments of 2Immunology and 3Cancer Biology, University of Texas and M. D. Anderson Cancer Center, Houston, Texas

Submitted 9 February 2007 ; accepted in final form 2 August 2007

Mitogen-activated protein kinase kinase kinase 3 (MEKK3) plays an essential role in embryonic angiogenesis, but its role in tumor growth and angiogenesis is unknown. In this study, we further investigated the role of MEKK3 in embryonic angiogenesis, tumor angiogenesis, and angiogenic factor production. We found that endothelial cells from Mekk3-deficient embryos showed defects in cell proliferation, apoptosis, and interactions with myocardium in the heart. We also found that MEKK3 is required for angiopoietin-1 (Ang1)-induced p38 and ERK5 activation. To study the role of MEKK3 in tumor growth and angiogenesis, we established both wild-type and Mekk3-deficient tumor-like embryonic stem cell lines and transplanted them subcutaneously into nude mice to assess their ability to grow and induce tumor angiogenesis. Mekk3-deficient tumors developed and grew similarly as control Mekk3 wild-type tumors and were also capable of inducing tumor angiogenesis. In addition, we found no differences in the production of VEGF in Mekk3-deficient tumors or embryos. Taken together, our results suggest that MEKK3 plays a critical role in Ang1/Tie2 signaling to control endothelial cell proliferation and survival and is required for endothelial cells to interact with the myocardium during early embryonic development. However, MEKK3 is not essential for tumor growth and angiogenesis.

cardiovascular; mitogen-activated protein kinase; embryonic development


Address for reprint requests and other correspondence: B. Su, Dept. of Immunobiology, Yale Univ. School of Medicine, 10 Amistad St., Rm. 401C, PO Box 208089, New Haven, CT 06520 (e-mail: bing.su{at}yale.edu)






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