Paclitaxel increases p21 synthesis and accumulation of its AKT-phosphorylated form in the cytoplasm of cancer cells.
CKI p21 is a regulator of cellular responses to microtubule damage induced by drugs such as paclitaxel (PTX). It mediates the G1 4N arrest postactivation of the spindle assembly checkpoint and protects cancer cells against PTX-induced cytotoxicity. We demonstrated here that low doses of PTX that are unable to activate the spindle assembly checkpoint, upregulate p21 by a p53-dependent pathway and induce its translocation to the cytoplasm. This cytoplasmic accumulation of p21 resulted from an AKT-dependent p21 phosphorylation leading to an association of p21 with 14-3-3. Furthermore, the cytoplasmic p21 accumulation observed in PTX-treated cells was inhibited by LY 294002, a specific PI-3 kinase inhibitor or by the expression of a dominant-negative AKT mutant. However, the kinase activity of AKT was unchanged in PTX-treated cells, suggesting that low doses of PTX could regulate p21 phosphorylation via inhibition of its dephosphorylation. As a functional consequence, we found that cytoplasmic accumulation of the phosphorylated form of p21 prevents the inhibitory effect of p21, enabling these cells to escape to the p53-dependent Gl/S and G2/M checkpoints.
Héliez
Christophe
C
LBCMCP, UMR CNRS 5088, IFR 109, Université Paul Sabatier, 31062 Toulouse, France.
Baricault
Laurent
L
Barboule
Nadia
N
Valette
Annie
A
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002453:Cell Cycle; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D008941:Spindle Apparatus / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel