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J. Biol. Chem., Vol. 283, Issue 12, 7754-7762, March 21, 2008

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TRAIL Stimulates Proliferation of Vascular Smooth Muscle Cells via Activation of NF-B and Induction of Insulin-like Growth Factor-1 Receptor^*

Mary M. Kavurma, Supported by a C. J. Martin Fellowship from the National Health and Medical Research Council of Australia (ID 300587)¹, Michael Schoppet², Yuri V. Bobryshev^¶, Levon M. Khachigian, and Martin R. Bennett

From the Division of Cardiovascular Medicine, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom and the Centre for Vascular Research and ^¶Faculty of Medicine, University of New South Wales, Kensington 2052, Australia

TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) is a multifunctional protein regulating homeostasis of the immune system, infection, autoimmune diseases, and apoptosis. However, its function in normal, nontransformed tissues is not clear. Here we show that TRAIL increases vascular smooth muscle cell (VSMC) proliferation in vitro, effects that can be blocked with neutralizing antibodies to TRAIL receptors DR4 and DcR1. In aortocoronary saphenous vein bypass grafts in vivo, TRAIL co-localizes with VSMC, proliferating cell nuclear antigen, and insulin-like growth factor type 1 receptor (IGF1R) expression but not active caspase-3. TRAIL is required for serum-inducible IGF1R expression, and antisense IGF1R inhibits TRAIL-induced VSMC proliferation. At 1 ng/ml, TRAIL stimulates IGF1R mRNA expression greater than insulin-like growth factor-1 and also activates the IGF1R promoter 7-fold. TRAIL-inducible IGF1R expression requires NF-B activation. Consistent with this, ammonium pyrrolidine dithiocarbamate, a pharmacological inhibitor of NF-B, blocks TRAIL-induced IGF1R expression, and p65 overexpression increases IGF1R protein levels. In addition, NF-B binds a novel TRAIL-responsive element on the IGF1R promoter. Our findings suggest that the biological functions of TRAIL in VSMC extend beyond its role in promoting apoptosis. Thus, TRAIL may play an important role in atherosclerosis by regulating IGF1R expression in VSMC in an NF-B-dependent manner.

Received for publication, August 20, 2007 , and in revised form, November 29, 2007.

^* This work was supported in part by British Heart Foundation Grant PG/04/005/16497 and RG/04/001 (to M. R. B.). 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.

² Supported by Deutsche Forschungsgemeinschaft Grant Ho 1875/5-2 and a grant from the Prof. Dr. A. Schmidtmann Foundation.

¹ To whom correspondence should be addressed: The Centre for Vascular Research, The University of New South Wales, Sydney, New South Wales 2052, Australia. Tel.: 61-2-9385-8109; Fax: 61-2-9385-1389; E-mail: m.kavurma{at}unsw.edu.au.

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