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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).

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