15-Deoxy-Delta(12,14)-prostaglandin J(2) impairs the functions of histone acetyltransferases through their insolubilization in cells.
The cyclopentenonic prostaglandin 15-deoxy-Delta(12,14)-PG J(2) (15d-PGJ(2)) is a metabolite derived from PGD(2). Although 15d-PGJ(2) has been demonstrated to be a potent ligand for peroxisome proliferator activated receptor gamma (PPARgamma), the functions are not fully understood. In order to examine the effect of 15d-PGJ(2) on histone acetyltransferases (HATs), several lines of cell including mouse embryonic fibroblast (MEF) cells were exposed to 15d-PGJ(2). Three types of HAT, p300, CREB-binding protein (CBP), and p300/CBP-associated factor (PCAF), selectively disappeared from the soluble fraction in time- and dose-dependent manners. Inversely, HATs in the insoluble fraction increased, suggesting their conformational changes. The decrease in the soluble form of HATs resulted in the attenuation of NF-kappaB-, p53-, and heat shock factor-dependent reporter gene expressions, implying that the insoluble HATs are inactive. The resultant insoluble PCAF and p300 seemed to be digested by proteasome, because proteasome inhibitors caused the accumulation of insoluble HATs. Taken together, these results indicate that 15d-PGJ(2) attenuates some gene expressions that require HATs. This inhibitory action of 15d-PGJ(2) on the function of HATs was independent of PPARgamma, because PPARgamma agonists could not mimick 15d-PGJ(2) and PPARgamma antagonists did not inhibit 15d-PGJ(2).
Department of Biochemistry, Nara Medical University, Shijo-Cho 840, Kashihara, Nara 634-8521, Japan.
Asako
A
Hironaka
Toshiaki
T
Morisugi
Tetsuji
T
Kawakami
Ikuko
I
Miyagi
Yasuharu
Y
Tanaka
D000818:Animals; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012995:Solubility; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D006360:Heat-Shock Proteins; D016328:NF-kappa B; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051548:Histone Acetyltransferases; D015230:Prostaglandin D2