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 Eischen; Dawn E Quelle

doi:10.1074/jbc.M609612200

Back

A novel nuclear interactor of ARF and MDM2 (NIAM) that maintains chromosomal stability

Journal article

Open access

Peer reviewed

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 Eischen and Dawn E Quelle

The Journal of biological chemistry, Vol.282(2), pp.1322-1333

01/12/2007

DOI: 10.1074/jbc.M609612200

PMID: 17110379

Files and links (1)

url

https://doi.org/10.1074/jbc.M609612200View

Published (Version of record) Open Access

Abstract

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.

Adenocarcinoma

Humans

Ubiquitin - metabolism

Intracellular Signaling Peptides and Proteins

Molecular Sequence Data

Breast Neoplasms

DNA-Binding Proteins - genetics

RNA, Messenger - metabolism

Chromosomes - physiology

Nuclear Proteins

Cell Division - physiology

DNA-Binding Proteins - metabolism

Animals

Cell Nucleus - metabolism

Tumor Suppressor Protein p53

Osteosarcoma

Ancrod

Cell Line, Tumor

Fibroblasts - cytology

Mice

Tumor Suppressor Protein p14ARF - metabolism

Proto-Oncogene Proteins c-mdm2 - metabolism

Details

Title: Subtitle: A novel nuclear interactor of ARF and MDM2 (NIAM) that maintains chromosomal stability
Creators: Van S Tompkins - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, 52242-1109, USA, and the Laboratoire de Genetique Cellulaire et Moleculaire, UPRES EA2622, Centre Hospitalier Universitaire de Poitiers, France
Jussara Hagen
April A Frazier
Tamara Lushnikova
Matthew P Fitzgerald
Anne di Tommaso
Veronique Ladeveze
Frederick E Domann
Christine M Eischen
Dawn E Quelle
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.282(2), pp.1322-1333
DOI: 10.1074/jbc.M609612200
PMID: 17110379
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: CA73612 / NCI NIH HHS T32 HL007344 / NHLBI NIH HHS CA98139 / NCI NIH HHS CA90367 / NCI NIH HHS R01 CA090367 / NCI NIH HHS
Language: English
Date published: 01/12/2007
Academic Unit: Molecular Physiology and Biophysics; Pathology; Surgery; Radiation Oncology; Neuroscience and Pharmacology
Record Identifier: 9984040597802771

Metrics

35 Record Views

36 Times Cited - Web of Science