© 1999 American Heart Association, Inc.
Original Contribution |
Molecular Mechanisms of Endothelin-1–Induced Cell-Cycle Progression
Involvement of Extracellular Signal-Regulated Kinase, Protein Kinase C, and Phosphatidylinositol 3-Kinase at Distinct Points
From the Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Correspondence to Etsu Suzuki, MD, PhD, The Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail suzuki-2im{at}h.u-tokyo.ac.jp
Abstract—Although it is well established that endothelin-1 (ET-1) has not only vasoconstrictive effects but also mitogenic effects, which seem to be implicated in vascular remodeling, little is known about the molecular mechanisms by which ET-1 induces cell-cycle progression. In this study, we examined the effects of ET-1 on the cell-cycle regulatory machinery, including cyclins, cyclin-dependent kinase (cdk), and cdk inhibitors in NIH3T3 cells. ET-1 increased cyclin D1 protein (5.1±1.9-fold increase, 8 hours after stimulation, P<0.05), cdk4 kinase activity (2.8±0. 5-fold increase, 12 hours after stimulation, P<0.01), and cdk2 kinase activity (2.1±0.4-fold increase, 16 hours after stimulation, P<0.05) in a time- and dose-dependent manner. ET-1–induced increase in cyclin D1 protein, and cdk4 kinase activity was not significantly inhibited by an inhibitor of the mitogen-activated protein kinase kinase 1/2, PD98059, nor by the protein kinase C inhibitor calphostin C, whereas ET-1–induced upregulation of cyclin D1 protein and cdk4 kinase activity was significantly inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002. In contrast, ET-1–induced activation of cdk2 kinase was significantly inhibited by PD98059, calphostin C, and LY294002. ET-1 increased 3H-thymidine uptake in a time-dependent fashion (0 hours, 4216±264 cpm per well; 8 hours, 5025±197 cpm per well; 16 hours, 9239±79 cpm per well, P<0.001 versus 0 hours). ET-1–induced increase in 3H-thymidine uptake was significantly inhibited by PD98059, calphostin C, and LY294002. These results suggest that ET-1–induced cell-cycle progression is, at least in part, mediated by the extracellular signal-regulated kinase, protein kinase C, and phosphatidylinositol 3-kinase and that those pathways may be involved in the progression of the cell cycle at distinct points.
Key Words: endothelin • kinase, extracellular signal-related • protein kinase C • phosphatidylinositol 3-kinase • cell cycle
This article has been cited by other articles:
 |
|
 |
|
  J. Milan, C. Charalambous, R. Elhag, T. C. Chen, W. Li, S. Guan, F. M. Hofman, and R. Zidovetzki Multiple signaling pathways are involved in endothelin-1-induced brain endothelial cell migration Am J Physiol Cell Physiol, July 1, 2006; 291(1): C155 - C164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. H. Dao, C. Bouvet, S. Moreau, P. Beaucage, R. Lariviere, M. J. Servant, J. de Champlain, and P. Moreau Endothelin is a dose-dependent trophic factor and a mitogen in small arteries in vivo Cardiovasc Res, July 1, 2006; 71(1): 61 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Mishra, Y. Wang, and M. S. Simonson Cell Cycle Signaling by Endothelin-1 Requires Src Nonreceptor Protein Tyrosine Kinase Mol. Pharmacol., June 1, 2005; 67(6): 2049 - 2056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. B. Tanowitz, H. Huang, L. A. Jelicks, M. Chandra, M. L. Loredo, L. M. Weiss, S. M. Factor, V. Shtutin, S. Mukherjee, R. N. Kitsis, et al. Role of Endothelin 1 in the Pathogenesis of Chronic Chagasic Heart Disease Infect. Immun., April 1, 2005; 73(4): 2496 - 2503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mukherjee, H. Huang, S. B. Petkova, C. Albanese, R. G. Pestell, V. L. Braunstein, G. J. Christ, M. Wittner, M. P. Lisanti, J. W. Berman, et al. Trypanosoma cruzi Infection Activates Extracellular Signal-Regulated Kinase in Cultured Endothelial and Smooth Muscle Cells Infect. Immun., September 1, 2004; 72(9): 5274 - 5282. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Huang, S. B. Petkova, A. W. Cohen, B. Bouzahzah, J. Chan, J.-n. Zhou, S. M. Factor, L. M. Weiss, M. Krishnamachary, S. Mukherjee, et al. Activation of Transcription Factors AP-1 and NF-{kappa}B in Murine Chagasic Myocarditis Infect. Immun., May 1, 2003; 71(5): 2859 - 2867. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. F. Luscher and M. Barton Endothelins and Endothelin Receptor Antagonists : Therapeutic Considerations for a Novel Class of Cardiovascular Drugs Circulation, November 7, 2000; 102(19): 2434 - 2440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. F. Hill, L. C. Katwa, B. R. Wamhoff, and M. Sturek Enhanced EndothelinA Receptor-Mediated Calcium Mobilization and Contraction in Organ Cultured Porcine Coronary Arteries J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 484 - 491. [Abstract] [Full Text]
|
|
|
|
 |
|
 D. Nagata, E. Suzuki, H. Nishimatsu, M. Yoshizumi, T. Mano, K. Walsh, M. Sata, M. Kakoki, A. Goto, M. Omata, et al. Cyclin A Downregulation and p21cip1 Upregulation Correlate With GATA-6-Induced Growth Arrest in Glomerular Mesangial Cells Circ. Res., October 13, 2000; 87(8): 699 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Suzuki, D. Nagata, M. Yoshizumi, M. Kakoki, A. Goto, M. Omata, and Y. Hirata 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 J. Biol. Chem., February 4, 2000; 275(5): 3637 - 3644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Nagata, E. Suzuki, H. Nishimatsu, H. Satonaka, A. Goto, M. Omata, and Y. Hirata Transcriptional Activation of the cyclin D1 Gene Is Mediated by Multiple Cis-Elements, Including SP1 Sites and a cAMP-responsive Element in Vascular Endothelial Cells J. Biol. Chem., January 5, 2001; 276(1): 662 - 669. [Abstract] [Full Text] [PDF]
|
|