The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence Journal Article

  

Authors:	Cheng, K.; Grisendi, S.; Clohessy, J. G.; Majid, S.; Bernardi, R.; Sportoletti, P.; Pandolfi, P. P.
Article Title:	The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence
Abstract:	Mutations leading to aberrant cytoplasmic localization of Nucleophosmin 1 (NPM1) have been recently identified as the most frequent genetic alteration in acute myelogenous leukemia. However, the oncogenic potential of this nucleophosmin mutant (NPMc+) has never been established, which casts doubt on its role in leukemogenesis. By performing classical transformation assays, we find that NPMc+, but not wild-type NPM, cooperates specifically with adenovirus E1A to transform primary mouse embryonic fibroblasts in soft agar. We demonstrate that NPMc+ blocks the p19Arf (Arf) induction elicited by E1A. Surprisingly, however, we find that NPMc+ induces cellular senescence and that E1A is able to overcome this response. We propose a model whereby the NPMc+ pro-senescence activity needs to be evaded for oncogenic transformation, even though NPMc+ can concomitantly blunt the Arf/p53 pathway. These findings identify for the first time NPMc+ as an oncogene and shed new unexpected light on its mechanism of action. © 2007 Nature Publishing Group All rights reserved.
Keywords:	controlled study; leukemia; acute granulocytic leukemia; mutation; nonhuman; mutant protein; protein localization; animal cell; mouse; animals; mice; embryo; protein p53; cancer model; cell transformation, neoplastic; nuclear proteins; oncogenes; cell transformation; leukemogenesis; fibroblast; tumor suppressor protein p53; cellular distribution; cytoplasm; gene silencing; adenovirus vector; senescence; arf protein; cyclin-dependent kinase inhibitor p16; cell aging; adenoviridae; nucleophosmin; adenovirus e1a proteins; arf; e1a; npmc+
Journal Title:	Oncogene
Volume:	26
Issue:	53
ISSN:	0950-9232
Publisher:	Nature Publishing Group
Date Published:	2007-11-22
Start Page:	7391
End Page:	7400
Language:	English
DOI:	10.1038/sj.onc.1210549
PUBMED:	17546053
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-36348993742&partnerID=40&md5=12190306cabba16f328011b81f7baa66
Notes:	--- - "Cited By (since 1996): 20" - "Export Date: 17 November 2011" - "CODEN: ONCNE" - "Source: Scopus"

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