ACTH upregulates MAP KINASE PHOSPHATASE-I (MKP-1) by a post-translational mechanism

BRION LAURA; MALOBERTI PAULA; GOMEZ NATALIA; COOKE MARIANA; MORI SEQUEIROS GARCÍA, MARÍA DE LAS MERCEDES; GOROSTIZAGA ALEJANDRA; ACQUIER ANDREA; PODESTA ERNESTO J; PAZ CRISTINA

San Diego

Congreso; XIV Adrenal Cortex Conference; 2010

MAP kinase phosphatase-1 (MKP-1) is a dual phosphatase that dephosphorylates MAP kinases. In Y1 cells, ACTH increases MKP-1 protein levels through a genomic effect. Here we analyze whether ACTH regulates MKP-1 protein levels also through a post- translational action and the functional role of this enzyme.  In Y1 cells overexpressing recombinant  Flag- MKP-1 protein, ACTH increased Flag- MKP-1 levels in a time-dependent fashion, with a maximal effect (8-fold) after 2 h. Moreover, ACTH-induced Flag- MKP-1 protein accumulation was reduced by the ERK upstream kinase inhibitor PD98059. In MA10-10 Leydig cells, hCG and 8Br-cAMP also increased Flag- MKP-1 protein levels through ERK172 action. MKP-1 overexpression reduced the hormonal effect on ERK1/2 activity, StAR promoter activity and steroidogenesis, while an RNAi against MKP-1 had opposite effects. We conclude that ACTH induces and ERK-dependent post translational modification of MKP-1 that increases its half-life. We conclude that ACTH induces an ERK-dependent post-translational modiification of MKP-1 protein levels contributes to the inactivation of ERK1/2 after the stimulation and consequently, regulates the hormonal action on steroidogenesis.