Carcinogenesis Advance Access originally published online on February 2, 2007
Carcinogenesis 2007 28(6):1163-1170; doi:10.1093/carcin/bgm025
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Nucleophosmin suppresses oncogene-induced apoptosis and senescence and enhances oncogenic cooperation in cells with genomic instability
1 Division of Experimental Hematology, Cincinnati Children’s Research Foundation, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
2 Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
3 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
* To whom correspondence should be addressed. Tel: +1 513 636 1152; Fax: +1 513 636 3768; Email: qishen.pang{at}cchmc.org
Cells from patients with genomic instability syndromes have high predisposition to cancer. However, little is known about whether these mutant cells have high susceptibility to oncogenic transformation. We have tested the hypothesis that a defect in maintaining genome integrity is necessary but not sufficient alone for oncogenic transformation and needs to collaborate with other signals in order to produce full oncogenic transformation. Using genetically matched primary cells deficient for the Fanconi complementation group C gene (Fancc) and the ataxia telangiectasia mutated gene (Atm), we found that certain forms of oncogenic activation and cooperation require a combination of genomic instability with increased expression of nucleophosmin (NPM) to prevent oncogenic stress-induced apoptosis or senescence. Intriguingly, co-expression of c-Myc and NPM leads to a synergistic increase in the proliferation rate in Fancc–/– or Atm–/– cells. Analysis of p53 stabilization and activation by c-Myc demonstrates that over-expression of NPM significantly reduces the accumulation of the activated p53 but not the stability of p53. Moreover, NPM is shown to enhance transforming activity of co-expressed Myc and Ras in wild-type and, to a greater degree, in Fancc–/– or Atm–/– cells, suggesting a role in oncogenic cooperation. Finally, a partial knockdown of NPM is sufficient to cause massive apoptosis in Fancc–/– or Atm–/– cells co-expressing c-Myc and Ras while sparing untransformed cells. Our study demonstrates a novel mechanism of NPM tumorigenesis by establishing NPM as a crucial inhibitor of oncogene-induced apoptosis and senescence.
Abbreviations: ATM, ataxia telangiectasia mutated gene; BrdU, bromodeoxyuridine; FA, Fanconi anemia; Fancc, Fanconi complementation group C gene; MEF, mouse embryo fibroblast; NPM, nucleophosmin; SA-ß-gal, senescence-associated-ß-galactosidase; siRNA, small interfering RNA; WT, wild type
Received October 25, 2006; revised January 23, 2007; accepted January 24, 2007.
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