Correlation between expression of 5-lipoxygenase-activating protein, 5-lipoxygenase, and cellular leukotriene synthesis.
Previous studies involving transfection of cDNAs for 5-lipoxygenase-activating protein (FLAP) and 5-lipoxygenase into osteosarcoma cells have shown that both these proteins are essential for leukotriene synthesis (Dixon, R. A. F., Diehl, R. E., Opas, E., Rands, E., Vickers, P. J., Evans, J. F., Gillard, J. W., and Miller, D. K. (1990) Nature 343, 282-284). In the present study we show that FLAP is present in a variety of cells known to produce leukotrienes, but is absent from a number of cells which do not synthesize leukotrienes. Furthermore, differentiation of the human promyelocytic HL-60 cell line towards granulocytic cells following exposure to dimethylsulfoxide is associated with the concurrent induction of both FLAP and 5-lipoxygenase and an increased capacity to synthesize leukotrienes. Cellular leukotriene synthesis in this system is functionally dependent on FLAP as shown by its inhibition by the leukotriene biosynthesis inhibitor MK-886, a compound which specifically binds to FLAP.
Reid
G K
GK
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada.
Kargman
S
S
Vickers
P J
PJ
Mancini
J A
JA
Léveillé
C
C
Ethier
D
D
Miller
D K
DK
Gillard
J W
JW
Dixon
R A
RA
Evans
J F
JF
D058927:5-Lipoxygenase-Activating Proteins; D000345:Affinity Labels; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics* / Q000502:physiology; D001386:Azides; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015870:Gene Expression; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007211:Indoles; D015473:Leukemia, Promyelocytic, Acute; D007975:Leukotriene B4 / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D010777:Photochemistry; D012333:RNA, Messenger / Q000378:metabolism; D013189:SRS-A / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D000345:Affinity Labels; C548593:Alox5ap protein, mouse; D001386:Azides; D002352:Carrier Proteins; D007211:Indoles; D008565:Membrane Proteins; D012333:RNA, Messenger; D013189:SRS-A; C062610:L 669083; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D004121:Dimethyl Sulfoxide