HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 10, 9417-9423, March 5, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/10/9417    most recent M312337200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tsunematsu, R. Articles by Nakayama, K. I. Search for Related Content PubMed PubMed Citation Articles by Tsunematsu, R. Articles by Nakayama, K. I. Social Bookmarking                      What's this?

Mouse Fbw7/Sel-10/Cdc4 Is Required for Notch Degradation during Vascular Development^*

Ryosuke Tsunematsu, Keiko Nakayama¶, Yuichi Oike||, Masaaki Nishiyama, Noriko Ishida, Shigetsugu Hatakeyama, Yasumasa Bessho**, Ryoichiro Kageyama**, Toshio Suda||, and Keiichi I. Nakayama

From the Department of Molecular and Cellular Biology and the ^¶Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, CREST, Japan Science and Technology Corp., Kawaguchi, Saitama 332-0012, the ^||Department of Cell Differentiation, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, and ^**Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan

Mammalian Fbw7 (also known as Sel-10, hCdc4, or hAgo) is the F-box protein component of an SCF (Skp1-Cul1-F-box protein-Rbx1)-type ubiquitin ligase, and the mouse Fbw7 is expressed prominently in the endothelial cell lineage of embryos. We generated mice deficient in Fbw7 and found that the embryos died in utero at embryonic day 10.5-11.5, manifesting marked abnormalities in vascular development. Vascular remodeling was impaired in the brain and yolk sac, and the major trunk veins were not formed. In vitro para-aortic splanchnopleural explant cultures from Fbw7^-/- embryos also manifested an impairment of vascular network formation. Notch4, which is the product of the proto-oncogene Int3 and an endothelial cell-specific mammalian isoform of Notch, accumulated in Fbw7^-/- embryos, resulting in an increased expression of Hey1, which encodes a transcriptional repressor that acts downstream of Notch signaling and is implicated in vascular development. Expression of Notch1, -2, or -3 or of cyclin E was unaffected in Fbw7^-/- embryos. Mammalian Fbw7 thus appears to play an indispensable role in negative regulation of the Notch4-Hey1 pathway and is required for vascular development.

Received for publication, December 11, 2003

^* This work was supported in part by a grant from the Ministry of Education, Science, Sports, and Culture of Japan and by a research grant from the Human Frontier Science Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. Tel.: 81-92-642-6815; Fax: 81-92-642-6819; E-mail: nakayak1{at}bioreg.kyushu-u.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?