DIETHYLUMBELLIFERYL PHOSPHATE INHIBITS STEROIDOGENESIS BY INTERFERING WITH A LONG-LIVED FACTOR ACTING BETWEEN PROTEIN-KINASE-A ACTIVATION AND INDUCTION OF THE STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR)

被引:24
作者
CHOI, YS
STOCCO, DM
FREEMAN, DA
机构
[1] UNIV OKLAHOMA,HLTH SCI CTR,DEPT INTERNAL MED,OKLAHOMA CITY,OK
[2] UNIV OKLAHOMA,HLTH SCI CTR,DEPT BIOCHEM & MOLEC BIOL,OKLAHOMA CITY,OK 73190
[3] DEPT VET AFFAIRS MED CTR,OKLAHOMA CITY,OK
[4] TEXAS TECH UNIV,HLTH SCI CTR,DEPT BIOCHEM & CELL BIOL,LUBBOCK,TX
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 1995年 / 234卷 / 02期
关键词
STEROIDOGENESIS; CHOLESTEROL TRANSPORT; MITOCHONDRIA; CAMP;
D O I
10.1111/j.1432-1033.1995.680_b.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Diethylumbelliferyl phosphate (DEUP) is an organophosphate cholesteryl ester hydrolase inhibitor that blocks steroidogenesis mainly by preventing cholesterol transport into the mitochondria of steroidogenic cells. In the present study, we show that DEUP blocks the cAMP-stimulated mitochondrial accumulation of the 30-kDa mitochondrial proteins (recently named steroidogenic acute regulatory StAR proteins) that are believed to be the cycloheximide-sensitive factors induced by trophic hormones and cAMP. Inhibition of mitochondrial StAR accumulation by DEUP is dose dependent and closely parallels inhibition of progesterone synthesis. Stimulated lactate production, another cAMP-dependent process in MA-10 cells, is also inhibited by DEUP, Inhibition of protein kinase A (PKA) action would explain the inhibition of these two unrelated processes. However, the cytosolic PKA activity of DEUP-treated MA-10 cells was normal. Moreover, the activity of purified PKA was unaffected by DEUP. The inhibition of StAR synthesis was not caused by a direct effect of DEUP on the labile proteins since DEUP-treated cells required more than 24 h to recover steroidogenic capacity after DEUP treatment. Further evidence that the synthesis of StAR was not directly affected was obtained using the constitutively active R2C cells. Progesterone synthesis by these cells also involves StAR, but neither StAR synthesis or steroid synthesis is sensitive to DEUP. Lactate formation in dibutyryl-cAMP-stimulated R2C cells is, however, sensitive to inhibition by DEUP. These data can be best explained by DEUP acting on a long-lived factor involved in the cAMP/PKA response pathway, but not involved in constitutive steroidogenesis.
引用
收藏
页码:680 / 685
页数:6
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