Affiliation:
1. Howard Hughes Medical Institute and Department of Genetics & Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105
Abstract
ABSTRACT
The Arf tumor suppressor inhibits cell cycle progression through both p53-dependent and p53-independent mechanisms, including interference with rRNA processing. Using tandem-affinity-tagged p19
Arf
, we purified Arf-associated proteins from mouse NIH 3T3 fibroblasts undergoing cell cycle arrest. Tagged p19
Arf
associated with nucleolar and ribosomal proteins, including nucleophosmin/B23 (NPM), a protein thought to foster the maturation of preribosomal particles. NPM is an abundant protein, only a minor fraction of which binds to p19
Arf
; however, a significant proportion of p19
Arf
associates with NPM. The interaction between p19
Arf
and NPM requires amino acid sequences at the Arf amino terminus, which are also required for Mdm2 binding, as well as the central acidic domain of NPM and an adjacent segment that regulates NPM oligomerization. The interaction between p19
Arf
and NPM occurs in primary mouse embryonic fibroblasts, including those lacking both
Mdm2
and
p53
. In an NIH 3T3 derivative cell line (MT-Arf) engineered to conditionally express an
Arf
transgene, induced p19
Arf
associates with NPM and colocalizes with it in high-molecular-weight complexes (2 to 5 MDa). An NPM mutant lacking its carboxyl-terminal nucleic acid-binding domain oligomerizes with endogenous NPM, inhibits p19
Arf
from entering into 2- to 5-MDa particles, and overrides the ability of p19
Arf
to retard rRNA processing.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
325 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献