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J. Biol. Chem., Vol. 279, Issue 35, 36698-36707, August 27, 2004

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Myc-ARF (Alternate Reading Frame) Interaction Inhibits the Functions of Myc^*

Abhishek Datta, Alo Nag, Wei Pan, Nissim Hay, Andrei L. Gartel, Oscar Colamonici¶, Yasuji Mori||, and Pradip Raychaudhuri**

From the Department of Biochemistry and Molecular Genetics and the ^||Section of Rheumatology, University of Illinois, Chicago, Illinois 60607 and the Department of Pharmacology, University of Illinois, Chicago, Illinois 60612

The tumor suppressor protein ARF (alternate reading frame) inhibits MDM2 to stabilize and activate the functions of p53. Here we provide evidence for an additional activity of ARF that attenuates cell cycle progression independently of p53 activation. We show that ARF interacts with c-Myc independently of MDM2 or p53. Consequently, ARF relocalizes c-Myc from the nucleoplasm to the nucleolus. Binding and relocalization by ARF correlate with an inhibition of the c-Myc-activated transcription in both p53-positive and -negative cells. Using inducible cell lines, we show that the wild type ARF, but not a mutant, inhibits expression of the c-Myc-induced genes before inhibiting S phase. Moreover, ARF inhibits Myc-induced progression into S phase in cells lacking p53 or expressing a defective p53, indicating that ARF inhibits the S phase stimulatory function of c-Myc independently of p53. Our results strongly suggest that cMyc is a bona fide target of ARF and that ARF attenuates c-Myc independently of the ARF-p53 axis.

Received for publication, November 10, 2003 , and in revised form, May 28, 2004.

^* This work was supported by NCI, National Institutes of Health, Grants CA88863 and CA100035 (to P. R.). 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.

^¶ Supported by National Institutes of Health Grants GM54709 and CA55079.

^** To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics (M/C 669), University of Illinois at Chicago, 900 S. Ashland Ave., Chicago, IL 60607. Tel.: 312-413-0255; Fax: 312-355-3847; E-mail: Pradip{at}uic.edu.

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