Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells
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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 p19(ARF) 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 p19(ARF) 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 p19(ARF) 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.
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 , vol 37 , no. 1 , pp. 31-39 . DOI: 10.3892/ijo_00000650
International Journal of Oncology
Copyright © Spandidos Publications 2010. All rights reserved. Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells Treanor, L., Bellamy, C., Harrison, D. J. & Prost, S. Jul 2010 In : International Journal of Oncology. 37, 1, p. 31-39. The original article is available at: http://dx.doi.org/10.3892/ijo_00000650