Drug-activated multiple pathways of defensin mRNA regulation in HL-60 cells are defined by reversed roles of participating protein kinases.
Defensin transcription in HL-60 promyelocytic leukemia cells is greatly enhanced during retinoic acid (RA)-induced differentiation. We have probed this regulatory pathway by selective modulation of various kinase activities. Induction was potentiated by elevated cAMP and attenuated by protein kinase C inhibition, entirely correlated to enhanced or blocked morphological differentiation, respectively. Yet, defensin mRNA was also induced in undifferentiated HL-60 cells, but not in others, by cAMP alone. By contrast, modulators that cooperated with RA had adverse effects on the normal capacity of dimethyl sulfoxide to up regulate these transcripts as well. Thus, defensin mRNA accumulation can be selectively uncoupled from maturation stage; and transcript levels may be regulated by multiple pathways, each independently acted upon by different chemical inducers.
Herwig
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Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Cornell University Graduate School of Medical Sciences, New York, NY 10021, USA.
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D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D023082:Defensins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis*; D014212:Tretinoin / Q000627:therapeutic use; D015854:Up-Regulation
D000970:Antineoplastic Agents; D001798:Blood Proteins; D023082:Defensins; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D014212:Tretinoin; D000242:Cyclic AMP; D011494:Protein Kinases