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J Biol Chem, Vol. 275, Issue 5, 3637-3644, February 4, 2000

Reentry into the Cell Cycle of Contact-inhibited Vascular Endothelial Cells by a Phosphatase Inhibitor
POSSIBLE INVOLVEMENT OF EXTRACELLULAR SIGNAL-REGULATED KINASE AND PHOSPHATIDYLINOSITOL 3-KINASE^*

Etsu Suzuki^§, Daisuke Nagata, Masao Yoshizumi^¶, Masao Kakoki, Atsuo Goto, Masao Omata, and Yasunobu Hirata

From the  Second Department of Internal Medicine and the ^¶ Department of Geriatrics, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Vascular endothelial cells are unique in that they exit from the cell cycle when they come into contact with each other. Although the phenomenon is called "contact inhibition," little is known about the cellular mechanisms involved. Here we show that the phosphatase inhibitor sodium orthovanadate (SOV) induced the reentry of contact-inhibited human umbilical vascular endothelial cells (HUVECs) into the cell cycle and that reentry was associated with activation of the extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI 3-K)/Akt pathways. SOV stimulated [³H]thymidine uptake of contact-inhibited HUVECs in a time- and dose-dependent manner. SOV-induced increase in [³H]thymidine uptake was significantly inhibited by the mitogen-activated protein kinase kinase inhibitor PD98059 and by the PI 3-K inhibitor LY294002. SOV also stimulated the expression of cyclin D1, cyclin E, and cyclin A, and the activity of CDK2 kinase, whereas it decreased the expression of p27^kip1. In marked contrast, growth media alone did not induce these changes. Furthermore, these SOV-induced changes were abolished by pretreatment with PD98059 and LY294002. SOV stimulated phosphorylation of ERK and Akt in contact-inhibited HUVECs, while growth media alone did not. This phosphorylation was associated with inhibition of phosphatase activity in the cells. Finally, overexpression of high cell density-enhanced protein tyrosine phosphatase 1 inhibited c-fos and cyclin A promoter activity. Taken together, our results suggest that in contact-inhibited HUVECs, increased phosphatase activity suppressed the ERK and PI 3-K/Akt pathways, resulting in exit from the cell cycle by down-regulation of cyclin D1, cyclin E, and cyclin A and by up-regulation of p27^kip1.

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^* This work was supported in part by Grants-in-aid for Scientific Research 09281206 and 10218202 from the Ministry of Education, Culture and Science of Japan (to Y. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The 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. Tel.: 81-3-3815-5411 (ext. 3072); Fax: 81-3-3814-0021; E-mail: suzuki-2im@h.u-tokyo.ac.jp.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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