Leukotriene receptors and mechanisms of signal transduction.
To better understand the mechanisms by which leukotriene tone is regulated, we have characterized the mechanisms of genetic regulation of 5-lipoxygenase in HL60 cells induced to differentiate with dimethyl sulfoxide (DMSO) and compared a number of rat and human 5-lipoxygenase introns. We demonstrate that differentiation of HL60 cells with DMSO results in coordinate induction of 5-LO and 5-LO activating protein (FLAP). The production of LTB4, 5-LO protein, 5-LO mRNa and FLAP RNA increased coordinately. However, two approaches demonstrated no increase in the initiation of transcription of 5-LO and FLAP pre-mRNA and no changes in the mRNA half lives. Moreover, cycloheximide inhibits the induction of the mRNAs and proteins. Thus, we suggest that 5-LO and FLAP are coordinately regulated in HL60 cells via mechanisms involving changes in RNA processing. To better understand potential mechanisms involved, we have cloned and sequenced several human 5-LO introns and compared them to analogous rat 5-LO introns. A number of regions of potential regulatory significances are conserved and may be important in controlling the rate of pre-mRNA processing.
Crooke
S T
ST
ISIS Pharmaceuticals, Carlsbad, California 92008.
Monia
B P
BP
Chiang
M Y
MY
Bennett
C F
CF
D058927:5-Lipoxygenase-Activating Proteins; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D004790:Enzyme Induction; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D015289:Leukotrienes / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008954:Models, Biological; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C548594:Alox5ap protein, rat; D002352:Carrier Proteins; D015289:Leukotrienes; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D001094:Arachidonate 5-Lipoxygenase