DRUG-ACTIVATED MULTIPLE PATHWAYS OF DEFENSIN MESSENGER-RNA REGULATIONIN HL-60 CELLS ARE DEFINED BY REVERSED ROLES OF PARTICIPATING PROTEIN-KINASES

Defensin transcription in HL-60 promyelocytic leukemia cells is greatl y enhanced during retinoic acid (RA)-induced differentiation. We have probed this regulatory pathway by selective modulation of various kina se activities. Induction was potentiated by elevated cAMP and attenuat ed by protein kinase C inhibition, entirely correlated to enhanced or blocked morphological differentiation, respectively. Yet, defensin mRN A was also induced in undifferentiated HL-60 cells, but not in others, by cAMP alone. By contrast, modulators that cooperated with RA had ad verse effects on the normal capacity of dimethyl sulfoxide to upregula te 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 d ifferent chemical inducers. (C) 1998 Elsevier Science Ltd. All rights reserved.