A novel nuclear interactor of ARF and Mdm2 (NIAM) that maintains chromosomal stability

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BlankSubmitted on October 11, 2006

Revised on November 14, 2006

Accepted on November 16, 2006

A novel nuclear interactor of ARF and Mdm2 (NIAM) that maintains chromosomal

stability

Van S. Tompkins, Jussara Hagen, April A. Frazier, Tamara Lushnikova, P.

Fitzgerald, Anne di Tommaso, Veronique Ladeveze, Frederick E. Domann,

M. Eischen, and Dawn E. Quelle

Pharmacology, University of Iowa College of Medicine, Iowa City, IA 52242-1109

Corresponding Author: dawn-quelle@...

The ARF tumor suppressor signals through p53 and other poorly defined

antiproliferative 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, due at least in part to Mdm2-mediated

ubiquitination and proteasomal degradation. When reintroduced into cells, NIAM

activates p53, causes a G1-phase cell cycle arrest, and collaborates with ARF in

an additive fashion to suppress proliferation. Notably, NIAM retains growth

inhibitory activity in cells lacking ARF and/or p53, and knockdown studies

reveal it is not essential for ARF-mediated growth inhibition. Thus, NIAM and

ARF act in separate antiproliferative pathways that intersect mechanistically

and suppress growth more effectively when jointly activated. Intriguingly,

silencing of NIAM accelerates chromosomal instability (CIN) and microarray

analyses show 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.