Published online before print July 17, 2003, doi: 10.1161/01.RES.0000086803.64109.9E
© 2003 American Heart Association, Inc.
Molecular Medicine |
Betacellulin and Amphiregulin Induce Upregulation of Cyclin D1 and DNA Synthesis Activity Through Differential Signaling Pathways in Vascular Smooth Muscle Cells
From the National Creative Research Initiatives Center for Endothelial Cells and Division of Molecular and Life Sciences (H.S.S., MSL., G.Y.K.), Pohang University of Science and Technology, Pohang, Korea; Department of Internal Medicine (H.J.L, I-K.L.), Keimyung University School of Medicine, Taegu, Korea; and the Department of Internal Medicine and Molecular Science (M.N., R.T., Y.M., S.Y.), Graduate School of Medicine, Osaka University, Yamada-Oka, Suita, Osaka, Japan.
Correspondence to Gou Young Koh, MD, PhD, National Creative Research Initiatives Center for Endothelial Cells, Division of Molecular and Life Sciences, Pohang University of Science and Technology, San 31, Hyoja-Dong, Pohang, 790-784, Republic of Korea. E-mail gykoh{at}postech.ac.kr
Activation of EGF receptors is closely involved in vascular proliferative diseases. The signaling mechanisms of EGF ligands, including betacellulin (BTC) and amphiregulin (AR), are poorly understood. We examined how BTC and AR induced DNA synthesis activity in primary cultures of human thoracic aortic smooth muscle cells (HTASMCs). BTC induced phosphorylation of all four EGF receptors present on HTASMCs: ErbB1, ErbB2, ErbB3, and ErbB4. BTC rapidly induced the phosphorylation of Akt, GSK3
/ß, and two FoxO factors, FKHR and AFX, in a dose- and time-dependent manner. BTC increased nuclear ß-catenin accumulation. BTC increased cyclin D1 mRNA, cyclin D1 protein, and DNA synthesis activity. Pretreatment with the phosphatidylinositol 3'-kinase (PI 3'-kinase) inhibitor wortmannin suppressed BTC-induced cyclin D1 mRNA and protein and DNA synthesis activity. In contrast, AR, a specific ErbB1 ligand, induced sustained ERK1/2 and Elk1 phosphorylation, increased cyclin D1 mRNA and protein, and increased DNA synthesis activity. AR did not produce any changes in Akt phosphorylation. Pretreatment with PD98059 suppressed AR-induced cyclin D1 mRNA and protein. Thus, the PI 3'-kinase/Akt/GSK/FoxO/ß-catenin pathway could be the major signaling cascade for BTC-induced upregulation of cyclin D1 protein, whereas a sustained ERK/Elk1 activation could be the major signaling cascade for AR-induced upregulation of cyclin D1 protein in HTASMCs. Moreover, immunohistochemical staining revealed that that BTC, ErbB1, and ErbB4 are upregulated in the plaques of human atherosclerotic coronary arteries. Taken together, BTC and AR could be potent growth factors in proliferative vascular diseases.
Key Words: betacellulin • amphiregulin • epidermal growth factor receptors • phosphatidylinositol 3'-kinase • extracellular signal-regulated kinase 1 and 2
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