Abstract
Retinoic acid (RA) induces cell growth arrest and differentiation through two families of nuclear receptors, the RARs and the RXRs. The phosphoinositide 3-kinase (PI3K)/Akt pathway also plays key roles in these processes, that is, cell cycle progression, cell differentiation and cell survival. We report that, in mouse embryocarcinoma cells (F9 cells), RA induces an early activation of PI3K and Akt via an increase in the expression of the p85α regulatory subunit. This effect is followed by an inhibition of Akt. Both effects require the integrity of the RA pathway as they are not observed in RA-resistant RARγ null cells. We propose a model through which RA induces a biphasic regulation of Akt with an activation participitating to the differentiation process, followed by an inhibition, which has been correlated to the RA-induced growth arrest.
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Acknowledgements
We are grateful to Bristol-Myers Squibb Pharmaceutical Research Institute for the gifts of the synthetic retinoids and to Professor P Chambon for providing the RARγ-−/− F9 cells. Special thanks to Gaétan Bour, Sebastien Lalevée and Nathalie Bruck for critically reading the manuscript. We also thank members of the cell culture facility for help. Caroline Pendaries and Gaétan Chicanne are strongly aknowledged for their help. This work was supported by funds from the Centre National de la Recherche scientifique (CNRS), the Institut National de la Recherche Médicale (INSERM) and the Association pour la Recherche sur le Cancer (ARC). JB was supported by the Ministère de la Recherche et de l’Enseignement Supérieur, by the Ligue Nationale contre le Cancer and by the Fondation pour la Recherche Médicale.
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Bastien, J., Plassat, JL., Payrastre, B. et al. The phosphoinositide 3-kinase/Akt pathway is essential for the retinoic acid-induced differentiation of F9 cells. Oncogene 25, 2040–2047 (2006). https://doi.org/10.1038/sj.onc.1209241
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DOI: https://doi.org/10.1038/sj.onc.1209241
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