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J. Biol. Chem., Vol. 282, Issue 2, 1322-1333, January 12, 2007

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A Novel Nuclear Interactor of ARF and MDM2 (NIAM) That Maintains Chromosomal Stability^*

Van S. Tompkins, Jussara Hagen, April A. Frazier, Tamara Lushnikova, Matthew P. Fitzgerald^¶, Anne di Tommaso^||, Veronique Ladeveze^||, Frederick E. Domann^¶, Christine M. Eischen¹, and Dawn E. Quelle²

From the Departments of Pharmacology and ^¶Radiation Oncology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242-1109, the Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198, and the ^||Laboratoire de Genetique Cellulaire et Moleculaire, UPRES EA2622, Universite de Poitiers and Centre Hospitalier Universitaire de Poitiers, 86022 Poitiers Cedex, France

The ARF tumor suppressor signals through p53 and other poorly defined anti-proliferative pathways to block carcinogenesis. In a search for new regulators of ARF signaling, we discovered a novel nuclear protein that we named NIAM (nuclear interactor of ARF and MDM2) for its ability to bind both ARF and the p53 antagonist MDM2. NIAM protein is normally expressed at low to undetectable levels in cells because of, at least in part, MDM2-mediated ubiquitination and proteasomal degradation. When reintroduced into cells, NIAM activated p53, caused a G₁ phase cell cycle arrest, and collaborated with ARF in an additive fashion to suppress proliferation. Notably, NIAM retains growth inhibitory activity in cells lacking ARF and/or p53, and knockdown experiments revealed that it is not essential for ARF-mediated growth inhibition. Thus, NIAM and ARF act in separate anti-proliferative pathways that intersect mechanistically and suppress growth more effectively when jointly activated. Intriguingly, silencing of NIAM accelerated chromosomal instability, and microarray analyses showed reduced NIAM mRNA expression in numerous primary human tumors. This study identifies a novel protein with tumor suppressor-like behaviors and functional links to ARF-MDM2-p53 signaling.

Received for publication, October 11, 2006 , and in revised form, November 14, 2006.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ144541 [GenBank] and DQ144542 [GenBank] .

^* This work was supported by the Roy J. Carver Trust; American Cancer Society Grant MGO-89378 (to D. E. Q.); and National Institutes of Health Grants CA73612 (to F. E. D.), CA98139 (to C. M. E.), and CA90367 (to D. E. Q.). 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.

¹ Leukemia & Lymphoma Society Scholar.

² To whom correspondence should be addressed: Dept. of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., Iowa City, IA 52242-1109. Tel.: 319-353-5749; Fax: 319-335-8930; E-mail: dawn-quelle{at}uiowa.edu.

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