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(Circulation Research. 2006;99:1338.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Wilms’ Tumor 1–Associating Protein Regulates the Proliferation of Vascular Smooth Muscle Cells

Theodore W. Small, Zuzana Bolender, Clara Bueno, Caroline O’Neil, Zengxuan Nong, Walter Rushlow, Nagalingham Rajakumar, Christopher Kandel, Jennifer Strong, Joaquin Madrenas, J. Geoffrey Pickering

From the Robarts Research Institute (T.W.S., Z.B., C.B., C.O., Z.N., C.K., J.S., J.M., J.G.P.), London Health Sciences Centre (J.M., J.G.P.), Departments of Medicine (Cardiology) (J.G.P.), Biochemistry (J.G.P.), Medical Biophysics (J.G.P.), Anatomy and Cell Biology (W.R., N.R.), and Microbiology and Immunology (J.M.), University of Western Ontario, London, Canada.

Correspondence to J. Geoffrey Pickering, MD PhD, London Health Sciences Centre, 339 Windermere Rd., London, Ontario N6A 5A5. E-mail gpickering{at}robarts.ca

Smooth muscle cells (SMCs) are called on to proliferate during vascular restructuring but must return to a nonproliferative state if remodeling is to appropriately terminate. To identify mediators of the reacquisition of replicative quiescence, we undertook gene expression screening in a uniquely plastic human SMC line. As proliferating SMCs shifted to a contractile and nonproliferative state, expression of TIMP-3, Axl, and KIAA0098 decreased whereas expression of complement C1s, cathepsin B, cellular repressor of E1A-activated genes increased. Wilms’ tumor 1-associating protein (WTAP), a nuclear constituent of unknown function, was also upregulated as SMCs became nonproliferative. Furthermore, WTAP in the intima of injured arteries was substantially upregulated in the late stages of repair. Introduction of WTAP complementary DNA into human SMCs inhibited their proliferation, with a corresponding decrease in DNA synthesis and an increase in apoptosis. Knocking down endogenous WTAP increased SMC proliferation, because of increased DNA synthesis and G₁/S phase transition, together with reduced apoptosis. WTAP was found to associate with the Wilms’ tumor-1 protein in human SMCs and WTAP overexpression inhibited the binding of WT1 to an oligonucleotide containing a consensus WT1 binding site, whereas WTAP knockdown accentuated this interaction. Expression of the WT1 target genes, amphiregulin and Bcl-2, was suppressed in WTAP-overexpressing SMCs and increased in WTAP-deficient SMCs. Moreover, exogenous amphiregulin rescued the antiproliferative effect of WTAP. These findings identify WTAP as a novel regulator of the cell cycle and cell survival and implicate a WTAP-WT1 axis as a novel pathway for controlling vascular SMC phenotype.

Key Words: amphiregulin • smooth muscle cells • Wilms’ tumor 1-associating protein • vascular smooth muscle cell proliferation

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