INVESTIGADORES
PODESTA Ernesto Jorge
artículos
Título:
MAPK Phosphatase-1 (MKP-1) Expression Is
Autor/es:
LAURA BRION, PAULA M. MALOBERTI, NATALIA V. GOMEZ, CECILIA PODEROSO ALEJANDRA B. GOROSTIZAGA, MARIA M. MORI SEQUEIROS GARCIA, ANDREA B. ACQUIER MARIANA COOKE, CARLOS F. MENDEZ, ERNESTO J. PODESTA, AND CRISTINA PAZ
Revista:
ENDOCRINOLOGY
Editorial:
ENDOCRINE SOC
Referencias:
Año: 2011 vol. 152
ISSN:
0013-7227
Resumen:
MAPK, sch as ERK1/2, exert profound effects on a variety of physiological processes. In steroidogenic
cells, ERK1/2 are involved in the expression and activation of steroidogenic acute regulatory protein,
which plays a central role in the regulation of steroidogenesis. In MA-10 Leydig cells, LH and chorionic
gonadotropin (CG) trigger transient ERK1/2 activation via protein kinase A, although the events that
lead toERK1/2inactivation arenotfully described. Here,wedescribethehormonalregulation ofMAPK
phosphatase-1 (MKP-1), an enzyme that inactivates MAPK, in MA-10 cells. In our experiments, human
CG (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 MAPK kinase/
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 posttranslational
level, protein phosphorylation being one of the mechanisms involved in this regulation. Our
study also demonstrates that MKP-1 overexpression reduces the effects of cAMP on ERK1/2 phosphorylation,
steroidogenic acute regulatory gene promoter activity, mRNA levels, and steroidogenesis,
whereas MKP-1 down-regulation by small interferingRNAproduces 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.