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Abstract
This study investigated the roles of the protein kinase C
(PKC) and protein kinase A (PKA) pathways in regulating
constitutive steroidogenesis and steroidogenic acute
regulatory (STAR; herein designated by its common name
StAR) protein in R2C Leydig tumor cells. Inhibition of PKC
and phospholipase C resulted in significant decreases in
steroid production, phosphorylation of cAMP responsive
element binding (CREB) protein and Star gene
transcription under basal conditions in R2C cells. These
observations were corroborated in MA-10 and mLTC-1 Leydig
tumor cell lines, where activation of PKC by
phorbol-12-myristate-13-acetate (PMA, 10 nM) increased
CREB phosphorylation and total StAR (tot-StAR) protein
expression. However, induction of StAR protein by PMA did
not result in the expected concomitant increase in
steroids because PKC failed to phosphorylate StAR
(P-StAR), the biologically active form of the protein.
However, in conjunction with PMA, minor increases in PKA
activity using sub-maximal doses of (Bu)2cAMP
(0.05-0.1 mM; a concentration range insufficient for
induction of StAR), were able to stimulate dramatic
increases in both P-StAR and steroid production. Human
chorionic gonadotropin (HCG; herein called hCG)
stimulation also resulted in a further enhancement in
P-StAR and progesterone production when added to PMA
treated MA-10 cells. Similar results for tot-StAR and
P-StAR expression were observed in primary cultures of
immature rat Leydig cells treated with PMA and sub-maximal
doses of (Bu)2cAMP. In summary, the present
study
demonstrates that basal activities of both PKC and PKA
play important roles in the constitutive steroidogenic
characteristics of R2C cells. This study also demonstrates
for the first time a role for PMA-induced PKC in StAR
protein regulation and the requirement for sub-maximal
doses of cAMP to produce steroids in Leydig cells.
Key words:
Kinases •
Leydig cells •
Progesterone •
Signal transduction •
Testosterone
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