A novel nuclear interactor of ARF and MDM2 (NIAM) that maintains chromosomal stability.
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.
Tompkins
Van S
VS
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.
Hagen
Jussara
J
Frazier
April A
AA
Lushnikova
Tamara
T
Fitzgerald
Matthew P
MP
di Tommaso
Anne
A
Ladeveze
Veronique
V
Domann
Frederick E
FE
Eischen
Christine M
CM
Quelle
Dawn E
DE
D000230:Adenocarcinoma; D000721:Ancrod; D000818:Animals; D001943:Breast Neoplasms; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002875:Chromosomes / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D012516:Osteosarcoma; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C517540:Niam protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; C517539:TBRG1 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D000721:Ancrod