Differential Taxol-dependent arrest of transformed and nontransformed cells in the G1 phase of the cell cycle, and specific-related mortality of transformed cells.
Taxol (paclitaxel) induces a microtubule hyperassembled state, and effectively blocks cells in mitosis. Here we report that Taxol also induces a stable late-G1 block in nontransformed REF-52 and WI-38 mammalian fibroblast cells, but not in T antigen-transformed cells of the same parental lineage. G1 arrest is characterized by partially dephosphorylated pRb, and inactive cdk2 kinase. Nontransformed cells recover normally from Taxol arrest. In contrast, T antigen transformed cells continue inappropriately past both G1 and G2-M in the presence of Taxol, and undergo a rapid death upon release. These results demonstrate a microtubule sensitive step in G1 regulation of nontransformed fibroblast cells. Also, Taxol selectively induces death of transformed cells, possibly because they slip the Taxol-dependent G1 arrest, as well as G2/M arrest, which are both specific to nontransformed cells.
Institut de Biologie Structurale Jean-Pierre Ebel (CEA-CNRS), Grenoble, France.
M O
MO
Trielli
P R
PR
Andreassen
F B
FB
Lacroix
R L
RL
Margolis
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002460:Cell Line; D002461:Cell Line, Transformed; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000032:analysis / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000032:analysis; D004791:Enzyme Inhibitors; D005347:Fibroblasts / Q000166:cytology*; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000032:analysis; D008870:Microtubules / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D011518:Proto-Oncogene Proteins; D051381:Rats; D016160:Retinoblastoma Protein / Q000032:analysis; D013539:Simian virus 40 / Q000276:immunology; D025521:Tumor Suppressor Proteins
D000952:Antigens, Polyomavirus Transforming; D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495892:Cdk2 protein, rat; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel; D015739:Nocodazole; D006918:Hydroxyurea