Inhibition of JNK2 disrupts anaphase and produces aneuploidy in mammalian cells.
The JNK family members JNK1 and JNK2 regulate tumor growth and are essential for transformation by oncogenes such as constitutively activated Ras. The mechanisms downstream of JNK that regulate cell cycle progression and transformation are unclear. Here we show that inhibition of JNK2, but not JNK1, with either a dominant-negative mutant, a pharmacological inhibitor, or RNA interference caused an accumulation of mammalian cells with 4N DNA content. When observed by immunofluorescence, these cells progressed to metaphase without apparent defects in spindle formation or chromosome alignment to the metaphase plate, suggesting that the 4N accumulation is a result of postmetaphase defects. Consistent with this prediction, when JNK activity was suppressed, we observed defects in central spindle formation and chromosome segregation during anaphase. In contrast, cyclin-dependent kinase 1 activity, cyclin B1 protein, and Polo-like kinase 1 protein turnover remained intact when JNK was inhibited. In addition, continued inhibition of JNK activity did not block reentry into subsequent cell cycles but instead resulted in polyploidy. This evidence suggests that JNK2 functions in maintaining the genomic stability of mammalian cells by signaling that is independent of cyclin-dependent kinase 1/cyclin B1 down-regulation.
MacCorkle
Rebecca A
RA
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Tan
Tse-Hua
TH
D000782:Aneuploidy; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D016466:CHO Cells; D018288:Carcinoma, Small Cell; D002478:Cells, Cultured; D006224:Cricetinae; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008175:Lung Neoplasms; D008322:Mammals; D008870:Microtubules / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology*; D034741:RNA, Small Interfering
C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D034741:RNA, Small Interfering; D048056:Mitogen-Activated Protein Kinase 9; D016203:CDC2 Protein Kinase; D020928:Mitogen-Activated Protein Kinases