Increased expression of the lipocalin 24p3 as an apoptotic mechanism for MK886.
MK886, a strong proapoptotic agent, is an inhibitor of 5-lipoxygenase (LOX) through binding to the 5-LOX-activating protein (FLAP). Although MK886-induced apoptosis is through a FLAP-independent pathway, the precise mechanisms are not understood. In the present study, a possible role of 24p3, a lipocalin, in MK886-induced apoptosis was investigated. Exposure of murine prolymphoid progenitor cells (FL5.12) to 20 microM MK886 for 16 h dramatically increased 24p3 mRNA and protein expression. Induction could also be achieved with another FLAP inhibitor, MK591. The induction of 24p3 by MK886 was dose- and time-dependent. The up-regulated 24p3 mRNA expression by MK886 was enhanced a further 3.1-fold by WY14643, an activator of peroxisome-proliferator-activated receptor alpha, whereas ciglitazone, an activator of peroxisome-proliferator-activated receptor gamma attenuated the MK886-induced 24p3 expression by more than 50%. Neither WY14643 nor ciglitazone alone had any effect on the expression of 24p3. The induction of 24p3 by MK886 was dependent on the synthesis of new protein(s), since cycloheximide, an inhibitor of protein synthesis, prevented this effect. In all cases, including the inhibition of MK886-induced 24p3 protein expression by stable transfection with antisense cDNA of 24p3, the extent of apoptosis closely paralleled 24p3 levels. Apoptosis induced by MK886, or enhanced by WY14643, was accompanied by the cleavage and activation of caspase-3. The overexpression of bcl-2 or bcl-x(L) in FL5.12 cells inhibited apoptosis induced by MK886 as well as the enhancement of apoptosis by WY14643. Thus 24p3 is an MK886-inducible gene and may play an important role in MK886-induced apoptosis.
Tong
Zhimin
Z
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712-0125, U.S.A.
Wu
Xuli
X
Kehrer
James P
JP
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D002273:Carcinogens / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D005786:Gene Expression Regulation; D007211:Indoles / Q000494:pharmacology*; D000071068:Lipocalin-2; D054834:Lipocalins; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D051379:Mice; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D002722:Chlorobenzenes
D000209:Acute-Phase Proteins; D002273:Carcinogens; D053148:Caspase 3; D020169:Caspases; D007211:Indoles; D000071068:Lipocalin-2; D054834:Lipocalins; D016859:Lipoxygenase Inhibitors; D015513:Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D013844:Thiazoles; D045162:Thiazolidinediones; C060893:MK-886; D002722:Chlorobenzenes; C071332:Lcn2 protein, mouse; C006253:pirinixic acid; C505409:Casp3 protein, mouse; C039671:ciglitazone