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¹ Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL and ² Department of Internal Medicine, Health Sciences Center, University of New Mexico, Albuquerque, NM

Requests for Reprints:Walker Wharton, Department of Internal Medicine, 5ACC, University of New Mexico Health Sciences Center, Albuquerque, NM 87131. Phone: (505) 272-9897; Fax: (505) 272-9912. E-mail: wwharton{at}salud.unm.edu

AG490, a member of the tryphostin family of protein kinase inhibitors, repressed G₀-G₁ traverse in BALB/c-3T3 cells. While the early induction of STAT activity was repressed by AG490, extracellular signal-regulated kinase (ERK) activation was unaffected and a pattern of gene expression suggested that cells exited G₀ in the presence of the inhibitor. Although AG490 did not alter the induction of cyclin D1 protein, neither cyclin D1- nor cyclin D3-associated kinase activity was observed in growth-inhibited cells. Surprisingly, p130 was partially phosphorylated, and E2F3A protein was expressed in mitogen-stimulated AG490-treated cells despite the lack of cyclin D-associated kinase activity. These data suggest that AG490 inhibits a cellular pathway required for mid-G₀-G₁ traverse that is located after the induction of early processes potentially mediated by E2F (although independent of cyclin D-associated kinase activity) but before the late G₁ increase in E2F-dependent transcription. Infection of AG490-treated cells with an E2F-1 adenovirus caused the induction of cyclin A, but could not overcome the drug-induced cell cycle arrest that was coincident with the repression of cyclin-dependent kinase 2 (cdk2)-associated kinase activation. We conclude that cdk2-associated kinase activity is modulated by a cellular process repressed by AG490. Furthermore, this cdk2-associated kinase activity is required for G₀-G₁ traverse in some role other than the regulation of E2F-dependent transcription.

Key Words: AG490 • E2F • p130 • cyclins

NIH Grant CA55652 (R. Jove) and NCI Grant CA78214 (W.D. Cress).

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.

Received 7/15/03; revised 10/22/03; accepted 11/ 3/03.

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