Differential effects of phorbol ester on signaling and gene expression in human leukemia cells.
Human U937 myeloid leukemia cells were treated with different concentrations of 12-O-tetradecanoylphorbol-13-acetate (TPA) to determine signals that contribute to growth arrest and differentiation. While 0.5 nM TPA had little if any effect, exposure of U937 cells to higher TPA concentrations (5-500 nM) revealed a complete growth arrest after 48 h. Cytosolic PKC activity decreased by 50% after exposure to 0.5 nM TPA and by 80 and 95% after stimulation with 5 nM and 50 nM TPA, respectively. Simultaneously, the PKC activity in the particulate fraction of U937 cells increased accordingly. These events were associated with induction of a differentiated monocytic phenotype. Expression of the c-myc gene was down-regulated and c-jun and c-fms transcripts increased following exposure to 5-500 nM TPA. In contrast, exposure to 0.5 nM TPA decreased c-myc expression and increased c-jun transcripts only transiently between 4 and 8 h while little if any effect was detectable on c-fms mRNA expression and subsequent differentiation. Taken together, these data suggest that a certain initial threshold of PKC activation is required for induction of a differentiated monocytic phenotype while beyond this threshold, a growth-arrested and differentiated state in these human leukemic cells can be maintained regardless of TPA concentrations.
Hass
R
R
Institute of Anatomy, University Clinic Charité, Berlin, Germany.
Prudovsky
I
I
Kruhøffer
M
M
D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016236:Genes, fms; D016758:Genes, jun; D016259:Genes, myc; D006801:Humans; D007700:Kinetics; D007951:Leukemia, Myeloid; D009000:Monocytes / Q000166:cytology; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate