Abstract
p8 is a stress-induced DNA-binding protein, biochemically related to the architectural chromatin binding HMG protein family and whose function is presently unknown. We obtained fibroblast from mice lacking p8 and found that p8 is involved in cell growth regulation and in apoptosis. p8−/− mouse embryonic fibroblasts (MEFs) grow more rapidly than p8+/+ MEFs. This might be explained by the higher intracellular level and activity of the Cdk2 and Cdk4 observed in p8−/− MEFs, which in turn may result, at least in part, from the concomitant decrease observed in the amount of cyclin-dependent kinase inhibitor p27. We also report that p8 mRNA expression is strongly activated in fibroblasts after cell growth arrest induced by serum deprivation or confluence. As expected, MEFs expressing p8 arrest their growth more rapidly after serum deprivation than MEFs lacking p8, which strongly suggests that p8 over-expression is implicated in cell growth arrest. On the other hand, p8+/+ MEFs are more sensitive than p8−/− MEFs to the apoptosis induced by adriamycin treatment. p53 might be involved, as p8 expression increases its intracellular amount and trans-activation capacity. Finally, demonstration that p53 is a negative trans-activator of p8 suggests the presence of a complex autoregulatory loop. In conclusion, p8 is a cell growth inhibitor that facilitates apoptosis induced in fibroblasts by DNA damage.
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Acknowledgements
We thank Drs H Cremer, S Garcia, M Monte and N Dusetti for insightful discussions and critical evaluation of the manuscript and to Dr A Levine for provide us the 10.1 and Val5 cells. Supported by grants from Société de Secours des Amis des Sciences and EMBO short fellowship (S Vasseur), Fondation pour la Recherche Médicale (A Hoffmeister), poste orange INSERM (A Garcia-Montero), and the Humboldt Foundation (GV Mallo). This work was supported by a grant from the Ligue de Lutte Contre le Cancer.
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Vasseur, S., Hoffmeister, A., Garcia-Montero, A. et al. p8-deficient fibroblasts grow more rapidly and are more resistant to adriamycin-induced apoptosis. Oncogene 21, 1685–1694 (2002). https://doi.org/10.1038/sj.onc.1205222
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DOI: https://doi.org/10.1038/sj.onc.1205222
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