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Human Tumor Suppressor ARF Impedes S-Phase Progression Independent of p53¹

Lineberger Comprehensive Cancer Center [W. G. Y., M. B., A. Z., Y. X.], Departments of Otolaryngology/Head and Neck Surgery [W. G. Y., A. Z.] and Biochemistry and Biophysics [W. G. Y., Y. X.], and Program in Molecular Biology and Biotechnology [W. G. Y., Y. X.], School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-3280, and Department of Functional Genetics, GlaxoSmithKline Pharmaceuticals, Research Triangle Park, North Carolina 27709 [J. E. B.]

Using alternative reading frames, the human ARF-INK4a locus encodes two unrelated proteins that both function in tumor suppression. p16^INK4a maintains the retinoblastoma protein in its growth-suppressive state through inhibition of cyclin D-dependent kinase activity, whereas ARF binds with MDM2 and stabilizes p53. The majority of the activity of ARF to date is ascribed to its ability to activate p53, resulting in a G₁ cell cycle arrest or apoptosis. We show here that ARF colocalizes with DNA replication protein A (RPA32) and that overexpression of ARF reduces the rate of DNA synthesis resulting in accumulation of an S-phase cell population. Impediment of DNA synthesis by ARF can occur and becomes more evident in the absence of p53. Hence, the biological consequence of ARF induction varies dependent on cellular p53 status, inducing predominantly a G₁ arrest or apoptosis in p53-positive cells or causing S-phase retardation when p53 function is comprised.

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