THE OBLIGATORY ACTION OF PROTEIN TYROSINE PHOSPHATASES IN ACTH-STIMULATED STEROIDOGENESIS IS EXERTED AT THE LEVEL OF StAR PROTEIN

C. PODEROSO, F. CORNEJO MACIEL, A. GOROSTIZAGA, P. BEY, C. PAZ, AND E. J. PODESTA´*

San Francisco, USA

Congreso; X Adrenal Cortex; 2002

A key regulatory step in the steroidogenic hormones signaling pathway is the  synthesis of steroidogenic acute regulatory protein (StAR). This protein  facilitates the delivery of cholesterol to the inner mitochondrial membrane, the  rate-limiting step in steroidogenesis. ACTH and LH pathway also includes  tyrosine dephosphorylation processes. Indeed, our previous studies have  demonstrated that both hormones increase protein tyrosine phosphatase (PTP)  activity by a PKA-dependent mechanism and that the action of PTPs is  required for the stimulation of steroid biosynthesis in adrenal and Leydig cells. In order to test the putative relationship between PTP activity and StAR  protein induction in adrenocortical cells, in the present study we evaluated  steroid production and StAR protein level in Y1 adrenocortical cells under  PTP inhibition. Phenylarsine oxide (PAO), a powerful cell permeable PTP  inhibitor, reduced ACTH-stimulated steroidogenesis in a concentrationdependent  fashion. A concentration of 2.5 mM of this compound inhibited  steroid synthesis in a 56% (ACTH=318+/-30, ACTH+PAO=145+/-18 ng  progesterone/mL, P<0.001) and also abrogated StAR protein induction.  Phenylarsine oxide reduced the protein level after 60 min and this effect still  remained at 120 min. A second PTP inhibitor, benzyl phosphonic acid, actino  by a different mechanism, reproduced PAO effects on both steroidogenesis and  StAR protein. Taken together, these results indicate that PTP activity  participates in StAR protein induction and led us to attribute to the  PKA-mediated PTP activation in steroidogenic systems a functional role, as  mediator of StAR protein induction.