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Onzin, a c-Myc-repressed target, promotes survival and transformation by modulating the Akt–Mdm2–p53 pathway

17 February 2021 EDITOR’S NOTE: Readers are alerted that in Figure 4B, the control panels appear to be duplicates. As this research was performed many years ago, the authors do not have the original data. However, it does not appear that these duplications affect the overall conclusions of the article.

Abstract

The c-Myc oncoprotein is a general transcription factor whose target genes dictate the c-Myc phenotype. One such target of c-Myc, ‘onzin’, is normally expressed at high levels in myeloid cells and is dramatically downregulated in response to c-Myc overexpression. We show here that short hairpin interfering RNA-mediated knockdown of endogenous onzin results in a reduced growth rate and a proapoptotic phenotype. In contrast, onzin overexpression in fibroblasts is associated with an increased growth rate, resistance to apoptotic stimuli, loss of the G2/M checkpoint, and tumorigenic conversion. Onzin-overexpressing cells fail to induce p53 in response to apoptotic stimuli and contain higher levels of the active, phosphorylated forms of Akt1 and, more strikingly, of Mdm2. Using yeast two-hybrid and coimmunoprecipitation assays, we show that onzin directly interacts with both proteins. Green fluorescent protein tagging also confirms directly that Akt1 and Mdm2 colocalize with onzin, although the precise subcellular distribution of each protein is dependent on its relative abundance. Collectively, our results identify onzin as a novel regulator of several p53-dependent aspects of the c-Myc phenotype via its dramatic effect on Mdm2. This is reminiscent of the c-Myc → p19ARF-- Mdm2 pathway and might function as a complementary arm to ensure the proper cellular response to oncogenic and/or apoptotic stimuli.

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  • 17 February 2021

    EDITOR’S NOTE: Readers are alerted that in Figure 4B, the control panels appear to be duplicates. As this research was performed many years ago, the authors do not have the original data. However, it does not appear that these duplications affect the overall conclusions of the article.

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Acknowledgements

We are grateful to Nissim Hay, Paul Coffer, and Christine Blattner for supplying plasmids. This work was supported by NIH grant HL33741 (to EVP) and by a post-doctoral fellowship award from The Research Advisory Committee of Children's Hospital of Pittsburgh to YL.

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Correspondence to Edward V Prochownik.

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Rogulski, K., Li, Y., Rothermund, K. et al. Onzin, a c-Myc-repressed target, promotes survival and transformation by modulating the Akt–Mdm2–p53 pathway. Oncogene 24, 7524–7541 (2005). https://doi.org/10.1038/sj.onc.1208897

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Keywords

  • c-Myc
  • p53
  • Mdm2
  • Akt
  • PTEN
  • Max
  • apoptosis
  • green fluorescent protein
  • PI-3 kinase
  • p19ARF
  • shRNA

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