ACTH UPREGULATES MAP KINASE PHOSPHATASE-1 (MKP-1) BY A POST-TRANSLATIONAL MECHANISM

BRION L; MALOBERTI P; GOMEZ N V; COOKE M; MORI SEQUEIROS GARCÍA M; GOROSTIZAGA A; ACQUIER AB; PODESTA EJ; PAZ C

San Diego, California, U.S.A.

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 MA-10 Leydig cells, hCG and 8Br-cAMP also increased Flag-MKP-1 protein levels through ERK1/2 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 an ERK-dependent post-translational modification of MKP-1 that increases its half-life. We also provide evidence that ACTH-triggered increase of MKP-1 protein levels contributes to the inactivation of ERK1/2 after the stimulation and consequently, regulates the hormonal action on steroidogenesis.