Nucleophosmin suppresses oncogene-induced apoptosis and senescence and enhances oncogenic cooperation in cells with genomic instability

June Li, Daniel P. Sejas, Sandeep Burma, David J. Chen, Qishen Pang

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1163-1170
Number of pages8
JournalCarcinogenesis
Volume28
Issue number6
DOIs
StatePublished - Jun 2007

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Genomic Instability
Oncogenes
Ataxia Telangiectasia
Apoptosis
Genes
nucleophosmin
Carcinogenesis
Genome
Neoplasms

ASJC Scopus subject areas

  • Cancer Research

Cite this

Nucleophosmin suppresses oncogene-induced apoptosis and senescence and enhances oncogenic cooperation in cells with genomic instability. / Li, June; Sejas, Daniel P.; Burma, Sandeep; Chen, David J.; Pang, Qishen.

In: Carcinogenesis, Vol. 28, No. 6, 06.2007, p. 1163-1170.

Research output: Contribution to journalArticle

Li, June ; Sejas, Daniel P. ; Burma, Sandeep ; Chen, David J. ; Pang, Qishen. / Nucleophosmin suppresses oncogene-induced apoptosis and senescence and enhances oncogenic cooperation in cells with genomic instability. In: Carcinogenesis. 2007 ; Vol. 28, No. 6. pp. 1163-1170.
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