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PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

Abstract

Protein kinase B (PKB/Akt) is ubiquitously expressed in cells. Phosphorylation of its multiple targets in response to various stimuli, including growth factors or cytokines, promotes cell survival and inhibits apoptosis. PKB is upregulated in many different cancers and a significant amount of the enzyme is present in its activated form. Here we show that PKB phosphorylates one of the anti-apoptotic proteins—transcription factor Twist-1 at Ser42. Cells expressing Twist-1 displayed inefficient p53 upregulation in response to DNA damage induced by γ-irradiation or the genotoxic drug adriamycin. This influenced the activation of p53 target genes such as p21Waf1 and Bax and led to aberrant cell-cycle regulation and the inhibition of apoptosis. The impaired induction of these p53 effector molecules is likely to be mediated by PKB-dependent phosphorylation of Twist-1 because, unlike the wild-type mutant, the Twist-1 S42A mutant did not confer cell resistance to DNA damage. Moreover, phosphorylation of Twist-1 at Ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of Twist-1 after promotion of survival during carcinogenesis.

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Acknowledgements

We thank S Bichet and A Bogucki for their help with immunohistochemistry and P King for critical comments on the article. This work was supported by the Novartis Research Foundation and the Swiss Cancer League Grant OCS 01667-02-2005 (to EG).

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Correspondence to B A Hemmings.

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Part of the results of this study has been used for the patent application EP 09 174 681.

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Vichalkovski, A., Gresko, E., Hess, D. et al. PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage. Oncogene 29, 3554–3565 (2010). https://doi.org/10.1038/onc.2010.115

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