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 S10 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 S10 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 S10 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 treatment and reverses the effect that atRA has on p27 binding to CDKs, on CDK activity, and on the expression of S phase genes.
Radu
Maria
M
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Soprano
Dianne R
DR
Soprano
Kenneth J
KJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D012694:Serine; D013997:Time Factors; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation
D000970:Antineoplastic Agents; C436291:CDKN1B protein, human; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012694:Serine; D014212:Tretinoin; D018844:Cyclin-Dependent Kinases; D046988:Proteasome Endopeptidase Complex