Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells

  • Authors:
    • Louise Treanor
    • Christopher Bellamy
    • David J. Harrison
    • Sandrine Prost
  • View Affiliations

  • Published online on: July 1, 2010     https://doi.org/10.3892/ijo_00000650
  • Pages: 31-39
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Abstract

We have previously reported that deletion of the retinoblastoma gene Rb leads to rapid but transient p53 stabilisation. We investigated here the pathways involved. We show that upon Rb-deletion dysregulated E2F activates p19ARF expression that localises in the nucleoli. There it interacts with MDM2, leading to P53 stabilisation. At the same time, ATR is activated, activating CHK1 that may phosphorylate P53 but also contribute to inhibition of MnSOD expression leading to accumulation of ROS (reactive oxygen species) and subsequent DNA injury, which in turn maintains ATR/CHK1 activated. However, from 72 h after Rb deletion, NPM interacts with P19ARF and concomitantly the interaction between p19ARF and MDM2 decreases leading to a return to P53 degradation. This occurs despite the persistence of the DNA damage response pathways. We therefore observe in primary cells not subjected to exogenous gene expression or exogenous DNA damaging treatment, activation of 2 concomitant pathways of activation of P53 that are dealt with in independent manner: an oncogenic pathway with rapid activation of ARF which is ‘switched off’ downstream of p19ARF activation after 72 h of induction and a DNA damage response pathway keeping a low level of transcriptionally active P53 sufficient to deal with a physiological elevation of oxidative DNA injury. A possible connection between the two pathways is discussed.

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July 2010
Volume 37 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Treanor L, Bellamy C, Harrison DJ and Prost S: Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells. Int J Oncol 37: 31-39, 2010
APA
Treanor, L., Bellamy, C., Harrison, D.J., & Prost, S. (2010). Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells. International Journal of Oncology, 37, 31-39. https://doi.org/10.3892/ijo_00000650
MLA
Treanor, L., Bellamy, C., Harrison, D. J., Prost, S."Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells". International Journal of Oncology 37.1 (2010): 31-39.
Chicago
Treanor, L., Bellamy, C., Harrison, D. J., Prost, S."Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells". International Journal of Oncology 37, no. 1 (2010): 31-39. https://doi.org/10.3892/ijo_00000650