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Journal of Virology, April 2004, p. 3304-3311, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3304-3311.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

p16^Ink4a Interferes with Abelson Virus Transformation by Enhancing Apoptosis

Zohar Sachs,^1,2,3 Norman E. Sharpless,^4, Ronald A. DePinho,⁴ and Naomi Rosenberg^1,2,3,5*

Department of Pathology,¹ Graduate Program in Immunology,² Medical Scientist Training Program,³ Department of Molecular Biology and Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111,⁵ Dana-Farber Cancer Center and Harvard Medical School, Boston, Massachusetts 02115⁴

Received 12 September 2003/ Accepted 5 December 2003

Pre-B-cell transformation by Abelson virus (Ab-MLV) is a multistep process in which primary transformants are stimulated to proliferate but subsequently undergo crisis, a period of erratic growth marked by high levels of apoptosis. Inactivation of the p53 tumor suppressor pathway is an important step in this process and can be accomplished by mutation of p53 or down-modulation of p19^Arf, a p53 regulatory protein. Consistent with these data, pre-B cells from either p53 or Ink4a/Arf null mice bypass crisis. However, the Ink4a/Arf locus encodes both p19^Arf and a second tumor suppressor, p16^Ink4a, that blocks cell cycle progression by inhibiting Cdk4/6. To determine if p16^Ink4a plays a role in Ab-MLV transformation, primary transformants derived from Arf^-/- and p16^Ink4a-/- mice were compared. A fraction of those derived from Arf^-/- animals underwent crisis, and even though all p16^Ink4a-/- primary transformants experienced crisis, these cells became established more readily than cells derived from +/+ mice. Analyses of Ink4a/Arf^-/- cells infected with a virus that expresses both v-Abl and p16^Ink4a revealed that p16^Ink4a expression does not alter cell cycle profiles but does increase the level of apoptosis in primary transformants. These results indicate that both products of the Ink4a/Arf locus influence Ab-MLV transformation and reveal that in addition to its well-recognized effects on the cell cycle, p16^Ink4a can suppress transformation by inducing apoptosis.

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* Corresponding author. Mailing address: Jaharis 808, Tufts Medical School, 150 Harrison Ave., Boston, MA 02111. Phone: (617) 636-2143. Fax: (617) 636-0337. E-mail: naomi.rosenberg{at}tufts.edu.

Present address: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599.

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Journal of Virology, April 2004, p. 3304-3311, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3304-3311.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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• Zimmerman, R. S., Rosenberg, N. (2008). Changes in p19Arf Localization Accompany Apoptotic Crisis during Pre-B-Cell Transformation by Abelson Murine Leukemia Virus. J. Virol. 82: 8383-8391 [Abstract] [Full Text]