Nucleophosmin (NPM) is a nucleolar phosphoprotein that binds the tumor suppressors p53 and p19Arf (Arf), and is thought to be indispensable for ribogenesis, cell proliferation and survival after DNA-damage. The NPM gene is the most frequent target of genetic alterations in leukemias and lymphomas, though its role in tumorigenesis is unknown. We report here the first characterization of a mouse NPM knock-out strain. Lack of NPM expression results into accumulation of DNA damage, activation of p53, widespread apoptosis and mid-stage embryonic lethality. Fibroblasts explanted from null embryos fail to grow and acquire rapidly a senescent phenoptype. Transfer of the NPM mutation into a p53-null background rescued apoptosis in vivo and fibroblast proliferation in vitro. Cells null for both p53 and NPM grow faster than control cells and are more susceptible to transformation by activated oncogenes, such as mutated Ras or overexpressed Myc. In the absence of NPM, Arf protein is excluded from nucleoli and is markedly less stable. Our data demonstrate that NPM regulates DNA integrity and, through Arf, inhibits cell proliferation, and are consistent with a putative tumor suppressive function of NPM.
|Titolo:||Nucleophosmin is required for DNA integrity and p19Arf protein stability|
|Parole Chiave:||DNA damage ; animal tissue ; apoptosis ; article ; carcinogenesis ; cell proliferation ; cell survival ; controlled study ; developmental stage ; embryo development ; embryo ; fibroblast ; gene mutation ; gene overexpression ; gene targeting ; human cell ; human ; in vitro study ; knockout mouse ; lethality ; leukemia ; lymphoma ; mouse ; nonhuman ; nucleolus ; oncogene ; phenotype ; priority journal ; protein DNA binding ; protein protein interaction ; protein stability ; ARF protein ; Myc protein ; Ras protein ; nucleophosmin ; phosphoprotein ; protein p19 ; protein p53 ; tumor suppressor protein|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||ott-2005|
|Digital Object Identifier (DOI):||10.1128/MCB.25.20.8874-8886.2005|
|Appare nelle tipologie:||01 - Articolo su periodico|