MAP Kinase Phosphatase-1 (MKP-1) expression is up-regulated by hCG/1 cAMP and modulates steroidogenesis in MA-10 Leydig cells.

BRION L ; MALOBERTI P; GOMEZ N; PODEROSO C; GOROSTIZAGA ALEJANDRA; MORI SEQUEIROS GARCÍA M; ACQUIER A; COOKE M; MENDEZ CF; PODESTA EJ; PAZ C

ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2011 p. 2665 - 2667

0013-7227

MAP kinases (MAPKs) such as ERK1/2 exert profound effects on a variety of physiologicalprocesses. In steroidogenic cells, ERK1/2 are involved in the expression and activation ofSteroidogenic Acute Regulatory (StAR) protein, which plays a central role in the regulation ofsteroidogenesis. In MA-10 Leydig cells, luteinizing hormone (LH) and chorionic gonadotropin (CG) trigger transient ERK1/2 activation via PKA, although the events that lead to ERK1/2 inactivation are not fully described. Here we describe the hormonal regulation of MAP kinase phosphatase-1 (MKP- 1), an enzyme that inactivates MAPKs, in MA-10 cells. In our experiments, hCG/cAMP stimulation rapidly and transiently increased MKP-1 mRNA levels by a transcriptional action. This effect was accompanied by an increase in protein levels in both nuclear and mitochondrial compartments. In cells transiently expressing flag-MKP-1 protein, hCG/cAMP promoted the accumulation of the recombinant protein in a time-dependent manner (10-fold at 1 h). Moreover, hCG/cAMP triggered ERK1/2-dependent MKP-1 phosphorylation. The blockade of cAMP-induced MEK/ERK activation abated MKP-1 phosphorylation but only partially reduced flag-MKP-1 protein accumulation. Together, these results suggest that hCG regulates MKP-1 at transcriptional and post-translational level, being protein phosphorylation one of the mechanisms involved in this regulation. Our study also demonstrates that MKP-1 over-expression reduces the effects of cAMP on ERK1/2 phosphorylation, StAR gene promoter activity, mRNA levels and steroidogenesis, whereas MKP-1 down-regulation by siRNA produces opposite effects. In summary, our data demonstrate that hCG regulates MKP-1 expression at multiple stages as a negative feedback regulatory mechanism to modulate the hormonal action on ERK1/2 activity and steroidogenesis.