Inhibition of the janus kinase family increases extracellular signal-regulated kinase 1/2 phosphorylation and causes endoreduplication.
The role of Janus-activated kinase (JAK) signaling in cell cycle transit and maintenance of genomic stability was determined in HL-60 myeloblastic leukemia cells. Inhibition of JAKs, all JAKs (JAK1, JAK2, JAK3, and tyrosine kinase 2), JAK2, or JAK3, caused a significant reduction in cell growth with a major G2-M arrest evident 24 hours after treatment. Targeting all JAKs also caused endoreduplication 48 and 72 hours after treatment. We discovered mitotic cells in both G2 (4N DNA) and G4 (8N DNA) subpopulations of cells treated with an inhibitor of all JAKs as detected by phosphorylated histone H3 expression. Treatment with inhibitors of just JAK2 or JAK3 drastically reduced such mitotic cells. We observed a complete blockage of IFN-gamma and interleukin-6-induced signal transducer and activator of transcription (STAT)-1 and STAT-3 response when all JAKs were inhibited. At the same time, we found baseline phosphorylated extracellular signal-regulated kinase (ERK) 1/2 to be elevated by JAK inhibition, particularly when all JAKs were inhibited. The G2-M arrest and endoreduplication induced by JAK inhibitors were reduced in cells pretreated with PD98059 to inhibit ERK. PD98059 also increased back the expression of the MAD2 cell cycle checkpoint protein that was down-regulated during "all JAKs inhibitor"-mediated endoreduplication. These data suggest that JAK signaling is needed for G2-M transit with inhibition of ERK.
Reiterer
Gudrun
G
Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853, USA.
Yen
Andrew
A
D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D064246:Mad2 Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D005419:Flavonoids; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D047428:Protein Kinase Inhibitors; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D011505:Protein-Tyrosine Kinases; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one