© 1995 American Heart Association, Inc.
Articles |
Rapamycin-FKBP Inhibits Cell Cycle Regulators of Proliferation in Vascular Smooth Muscle Cells
From the Cardiovascular Institute, Molecular Medicine Program, Department of Medicine, and Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, NY.
Correspondence to Andrew R. Marks, Box 1269, Mount Sinai School of Medicine, One Gustave L. Levy Pl, New York, NY 10029.
Abstract Multiple growth factors can stimulate quiescent vascular smooth muscle cells to exit from G0 and reenter the cell cycle. The macrolide antibiotic rapamycin, bound to its cytosolic receptor FKBP, is an immunosuppressant and a potent inhibitor of cellular proliferation. In the present study, the antiproliferative effects of rapamycin on human and rat vascular smooth muscle cells were examined and compared with the effects of a related immunosuppressant, FK520. In vascular smooth muscle cells, rapamycin, at concentrations as low as 1 ng/mL, inhibited DNA synthesis and cell growth. FK520, an analogue of the immunosuppressant FK506, is structurally related to rapamycin and binds to FKBP but did not inhibit vascular smooth muscle cell growth. Molar excesses of FK520 blocked the antiproliferative effects of rapamycin, indicating that the effects of rapamycin required binding to FKBP. Rapamycin-FKBP inhibited retinoblastoma protein phosphorylation at the G1/S transition. This inhibition of retinoblastoma protein phosphorylation was associated with a decrease in p33cdk2 kinase activity. These observations suggest that rapamycin, but not FK520, inhibits vascular smooth muscle cell proliferation by reducing cell-cycle kinase activity.
Key Words: immunophilin • accelerated arteriosclerosis • antiproliferation • transplantation • FK506
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J. Sun, S. O. Marx, H.-J. Chen, M. Poon, A. R. Marks, and L. E. Rabbani Role for p27Kip1 in Vascular Smooth Muscle Cell Migration Circulation, June 19, 2001; 103(24): 2967 - 2972. [Abstract] [Full Text] [PDF]
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S. Huang, L. N. Liu, H. Hosoi, M. B. Dilling, T. Shikata, and P. J. Houghton p53/p21CIP1 Cooperate in Enforcing Rapamycin-induced G1 Arrest and Determine the Cellular Response to Rapamycin Cancer Res., April 1, 2001; 61(8): 3373 - 3381. [Abstract] [Full Text]
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J. E. Sousa, M. A. Costa, A. Abizaid, A. S. Abizaid, F. Feres, I. M. F. Pinto, A. C. Seixas, R. Staico, L. A. Mattos, A. G. M. R. Sousa, et al. Lack of Neointimal Proliferation After Implantation of Sirolimus-Coated Stents in Human Coronary Arteries : A Quantitative Coronary Angiography and Three-Dimensional Intravascular Ultrasound Study Circulation, January 16, 2001; 103(2): 192 - 195. [Abstract] [Full Text] [PDF]
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C. Duan, M. B. Liimatta, and O. L. Bottum Insulin-like Growth Factor (IGF)-I Regulates IGF-binding Protein-5 Gene Expression through the Phosphatidylinositol 3-Kinase, Protein Kinase B/Akt, and p70 S6 Kinase Signaling Pathway J. Biol. Chem., December 24, 1999; 274(52): 37147 - 37153. [Abstract] [Full Text] [PDF]
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M. Grewe, F. Gansauge, R. M. Schmid, G. Adler, and T. Seufferlein Regulation of Cell Growth and Cyclin D1 Expression by the Constitutively Active FRAP-p70s6K Pathway in Human Pancreatic Cancer Cells Cancer Res., August 1, 1999; 59(15): 3581 - 3587. [Abstract] [Full Text] [PDF]
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J. F. GUMMERT, T. IKONEN, and R. E. MORRIS Newer Immunosuppressive Drugs: A Review J. Am. Soc. Nephrol., June 1, 1999; 10(6): 1366 - 1380. [Abstract] [Full Text]
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R. Gallo, A. Padurean, T. Jayaraman, S. Marx, M. Roque, S. Adelman, J. Chesebro, J. Fallon, V. Fuster, A. Marks, et al. Inhibition of Intimal Thickening After Balloon Angioplasty in Porcine Coronary Arteries by Targeting Regulators of the Cell Cycle Circulation, April 27, 1999; 99(16): 2164 - 2170. [Abstract] [Full Text] [PDF]
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J.-M. Li and G. Brooks Cell cycle regulatory molecules (cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors) and the cardiovascular system; potential targets for therapy? Eur. Heart J., March 2, 1999; 20(6): 406 - 420. [PDF]
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H. Hosoi, M. B. Dilling, T. Shikata, L. N. Liu, L. Shu, R. A. Ashmun, G. S. Germain, R. T. Abraham, and P. J. Houghton Rapamycin Causes Poorly Reversible Inhibition of mTOR and Induces p53-independent Apoptosis in Human Rhabdomyosarcoma Cells Cancer Res., February 1, 1999; 59(4): 886 - 894. [Abstract] [Full Text] [PDF]
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R. C. Braun-Dullaeus, M. J. Mann, and V. J. Dzau Cell Cycle Progression : New Therapeutic Target for Vascular Proliferative Disease Circulation, July 7, 1998; 98(1): 82 - 89. [Abstract] [Full Text] [PDF]
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 J. Laliberte, A. Yee, Y. Xiong, and B. S. Mitchell Effects of Guanine Nucleotide Depletion on Cell Cycle Progression in Human T Lymphocytes Blood, April 15, 1998; 91(8): 2896 - 2904. [Abstract] [Full Text] [PDF]
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 T. C. Major and J. A. Keiser Inhibition of Cell Growth: Effects of the Tyrosine Kinase Inhibitor CGP 53716 J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 402 - 410. [Abstract] [Full Text]
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M. Weis and W. von Scheidt Cardiac Allograft Vasculopathy : A Review Circulation, September 16, 1997; 96(6): 2069 - 2077. [Abstract] [Full Text]
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M. O. Boluyt, J.-S. Zheng, A. Younes, X. Long, L. O'Neill, H. Silverman, E. G. Lakatta, and M. T. Crow Rapamycin Inhibits {alpha}1-Adrenergic Receptor–Stimulated Cardiac Myocyte Hypertrophy but Not Activation of Hypertrophy-Associated Genes : Evidence for Involvement of p70 S6 Kinase Circ. Res., August 19, 1997; 81(2): 176 - 186. [Abstract] [Full Text]
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N. L. Zhu, L. Wu, P. X. Liu, E. M. Gordon, W. F. Anderson, V. A. Starnes, and F. L. Hall Downregulation of Cyclin G1 Expression by Retrovirus-Mediated Antisense Gene Transfer Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation Circulation, July 15, 1997; 96(2): 628 - 635. [Abstract] [Full Text]
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D. J. Withers, T. Seufferlein, D. Mann, B. Garcia, N. Jones, and E. Rozengurt Rapamycin Dissociates p70S6K Activation from DNA Synthesis Stimulated by Bombesin and Insulin in Swiss 3T3 Cells J. Biol. Chem., January 24, 1997; 272(4): 2509 - 2514. [Abstract] [Full Text] [PDF]
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M. Higaki, H. Sakaue, W. Ogawa, M. Kasuga, and K. Shimokado Phosphatidylinositol 3-Kinase-independent Signal Transduction Pathway for Platelet-derived Growth Factor-induced Chemotaxis J. Biol. Chem., November 15, 1996; 271(46): 29342 - 29346. [Abstract] [Full Text] [PDF]
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H. Koyama, Y. Nishizawa, M. Hosoi, S. Fukumoto, K. Kogawa, A. Shioi, and H. Morii The Fumagillin Analogue TNP-470 Inhibits DNA Synthesis of Vascular Smooth Muscle Cells Stimulated by Platelet-Derived Growth Factor and Insulin-like Growth Factor-I: Possible Involvement of Cyclin-Dependent Kinase 2 Circ. Res., October 1, 1996; 79(4): 757 - 764. [Abstract] [Full Text]
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J. Sadoshima and S. Izumo Rapamycin Selectively Inhibits Angiotensin II–Induced Increase in Protein Synthesis in Cardiac Myocytes In Vitro : Potential Role of 70-kD S6 Kinase in Angiotensin II– Induced Cardiac Hypertrophy Circ. Res., December 1, 1995; 77(6): 1040 - 1052. [Abstract] [Full Text]
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F. Peiretti, S. Lopez, P. Deprez-Beauclair, B. Bonardo, I. Juhan-Vague, and G. Nalbone Inhibition of p70S6 Kinase during Transforming Growth Factor-beta 1/Vitamin D3-induced Monocyte Differentiation of HL-60 Cells Allows Tumor Necrosis Factor-alpha to Stimulate Plasminogen Activator Inhibitor-1 Synthesis J. Biol. Chem., August 17, 2001; 276(34): 32214 - 32219. [Abstract] [Full Text] [PDF]
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M. J. Kluk and T. Hla Role of the Sphingosine 1-Phosphate Receptor EDG-1 in Vascular Smooth Muscle Cell Proliferation and Migration Circ. Res., September 14, 2001; 89(6): 496 - 502. [Abstract] [Full Text] [PDF]
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