The ERK signaling cascade inhibits gonadotropin-stimulated steroidogenesis.
The response of granulosa cells to luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is mediated mainly by cAMP/protein kinase A (PKA) signaling. Notably, the activity of the extracellular signal-regulated kinase (ERK) signaling cascade is elevated in response to these stimuli as well. We studied the involvement of the ERK cascade in LH- and FSH-induced steroidogenesis in two granulosa-derived cell lines, rLHR-4 and rFSHR-17, respectively. We found that stimulation of these cells with the appropriate gonadotropin induced ERK activation as well as progesterone production downstream of PKA. Inhibition of ERK activity enhanced gonadotropin-stimulated progesterone production, which was correlated with increased expression of the steroidogenic acute regulatory protein (StAR), a key regulator of progesterone synthesis. Therefore, it is likely that gonadotropin-stimulated progesterone formation is regulated by a pathway that includes PKA and StAR, and this process is down-regulated by ERK, due to attenuation of StAR expression. Our results suggest that activation of PKA signaling by gonadotropins not only induces steroidogenesis but also activates down-regulation machinery involving the ERK cascade. The activation of ERK by gonadotropins as well as by other agents may be a key mechanism for the modulation of gonadotropin-induced steroidogenesis.
Departments of Biological Regulation and Molecular Cell Biology, the Weizmann Institute of Science, Rehovot 71600, Israel. rony.seger@weizmann.ac.il
R
R
Seger
T
T
Hanoch
R
R
Rosenberg
A
A
Dantes
W E
WE
Merz
J F
JF
Strauss
A
A
Amsterdam
D000818:Animals; D002460:Cell Line; D006063:Chorionic Gonadotropin / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006062:Gonadotropins / Q000378:metabolism*; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011374:Progesterone / Q000096:biosynthesis / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D013256:Steroids / Q000096:biosynthesis*; D013997:Time Factors; D014162:Transfection; D000098682:Steroidogenic Acute Regulatory Protein
D006063:Chorionic Gonadotropin; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006062:Gonadotropins; D010750:Phosphoproteins; D013256:Steroids; D000098682:Steroidogenic Acute Regulatory Protein; D005576:Colforsin; D011374:Progesterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one