S10 phosphorylation of p27 mediates atRA induced growth arrest in ovarian carcinoma cell lines

All trans retinoic acid (atRA) has been shown to inhibit the growth of CAOV3 ovarian carcinoma cells and to elevate the level of p27 cyclin-dependent kinase inhibitor. We report here that phosphorylation at S 10 residue is an important event in mediating p27 role in atRA induced growth arrest. atRA treatment of atRA sensitive CAOV3 cells increases the levels of S 10 phospho-p27 in both nuclear and cytoplasmic cell compartments. This increase is accompanied by a decrease in the levels of skp2 protein. This effect was not observed in SKOV3 cells which are resistant to atRA growth inhibitory effect. An A10-p27 mutant that cannot be phosphorylated at S 10 induces a dominant negative effect on the atRA effect on the levels and activity of endogenous p27. Overexpression of A10-p27 mutant renders CAOV3 cells more resistant to atRA treatmentand reverses the effect that atRA has on p27 binding to CDKs, on CDK activity,and on the expression of S phase genes.