Ubiquitination of, and sumoylation by, the Arf tumor suppressor.
Isr Med Assoc J
; 8(4): 249-51, 2006 Apr.
Article
de En
| MEDLINE
| ID: mdl-16671360
ABSTRACT
The Ink4a-Arf locus, which encodes two distinct tumor suppressor proteins, is inactivated in many cancers. Whereas p16Ink4a is an inhibitor of cyclin D-dependent kinases, p19Arf (p14ARF in humans) antagonizes the E3 ubiquitin protein ligase activity of Mdm2 to activate p53. We now recognize that Arf functions in both p53-dependent and -independent modes to counteract hyper-proliferative signals originating from proto-oncogene activation, but its p53-independent activities remain poorly understood. Arf proteins are highly basic (> 20% arginine content, pl > 12) and predominantly localize within nucleoli in physical association with an abundant acidic protein, nucleophosmin (NPM/B23). When bound to NPM, Arf proteins are relatively stable with half-lives of 6-8 hours. Although mouse p19Arf contains only a single lysine residue and human p14ARF has none, both proteins are N-terminally ubiquitinated and degraded in proteasomes. Through as yet uncharacterized mechanisms, p19Arf induces p53-independent sumoylation of a variety of cellular target proteins with which it interacts, including both Mdm2 and NPM. A naturally occurring NPM mutant (NPMc) expressed in myeloid leukemia cells redirects both wild-type NPM and p19Arf to the cytoplasm, inhibits Arf-induced sumoylation, and attenuates p53 activity. Thus, ubiquitination and sumoylation can each influence Arf tumor suppressor activity.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéine p53 suppresseur de tumeur
/
Inhibiteur p16 de kinase cycline-dépendante
/
Protéine p14(ARF) suppresseur de tumeur
/
Ubiquitine
Limites:
Humans
Langue:
En
Journal:
Isr Med Assoc J
Sujet du journal:
MEDICINA
Année:
2006
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique