Inhibition of c-jun causes reversible proliferative arrest and withdrawal from the cell cycle.
We studied the effect of c-jun depletion in Friend murine erythroleukemia (F-MEL) cells stably transfected with a plasmid that allowed for the glucocorticoid-mediated conditional expression of c-jun antisense sequences. The c-jun cDNA used for the construction of the vector was modified so as to prevent the nonspecific targeting of junB and junD transcripts. High level and rapid induction of c-jun antisense transcripts was achieved with as little as 10(-8) mol/L dexamethasone (DEX) and resulted in a 80% to 90% reduction in c-jun protein levels. The continuous exposure of the transfected cells to DEX inhibited growth by greater than 85% over a 5-day period, whereas DEX had no effect on the growth rate of control F-MEL cells. This proliferative block was associated with a reversible accumulation of cells with a 2n DNA content. When these cells were recultured in the absence of DEX, c-jun protein rapidly reappeared and the immediate early response genes egr-1, junB, and c-myc were transiently expressed. Thus, inhibition of c-jun protein causes logarithmically growing cells to leave the cell cycle and to enter a state closely resembling, if not identical to, G0. These results underscore the importance of c-jun in maintaining cellular proliferation and provide additional evidence for the participation of proto-oncogenes in cell cycle control.
Smith
M J
MJ
Division of Hematology/Oncology, University of Michigan School of Medicine, Ann Arbor 48109.
Prochownik
E V
EV
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D016373:DNA, Antisense; D003907:Dexamethasone / Q000494:pharmacology*; D016758:Genes, jun / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D007942:Leukemia, Experimental; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D010957:Plasmids; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects
D016373:DNA, Antisense; D016755:Proto-Oncogene Proteins c-jun; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D003907:Dexamethasone; D008727:Methotrexate