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Published on: November 15, 2013
The ERK signaling cascade inhibits gonadotropin-stimulated steroidogenesis
R Seger1, T Hanoch, R Rosenberg
1Departments of Biological Regulation and Molecular Cell Biology, the Weizmann Institute of Science, Rehovot 71600, Israel. rony.seger@weizmann.ac.il
Abstract:
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.
Insights
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulate progesterone production in granulosa cells via PKA signaling. However, the ERK pathway down-regulates this process by reducing steroidogenic acute regulatory protein (StAR) expression.
Area of Science:
- Reproductive Endocrinology
- Cell Signaling
- Molecular Biology
Background:
- Granulosa cell response to LH and FSH is primarily mediated by cAMP/protein kinase A (PKA) signaling.
- Extracellular signal-regulated kinase (ERK) signaling is also activated by these gonadotropins.
Purpose of the Study:
- To investigate the role of the ERK signaling cascade in LH- and FSH-induced steroidogenesis in granulosa-derived cell lines.
- To elucidate the regulatory mechanisms of gonadotropin-stimulated progesterone production.
Main Methods:
- Utilized two granulosa-derived cell lines (rLHR-4 and rFSHR-17).
- Stimulated cells with appropriate gonadotropins (LH or FSH).
- Assessed ERK activation, progesterone production, and steroidogenic acute regulatory protein (StAR) expression.
- Inhibited ERK activity to observe effects on steroidogenesis.
Main Results:
- Gonadotropin stimulation induced both ERK activation and progesterone production downstream of PKA.
- Inhibition of ERK activity enhanced gonadotropin-stimulated progesterone production.
- Enhanced progesterone production correlated with increased StAR expression upon ERK inhibition.
Conclusions:
- Gonadotropin-stimulated progesterone formation involves PKA and StAR, with ERK acting as a down-regulator by attenuating StAR expression.
- Activation of PKA signaling by gonadotropins not only induces steroidogenesis but also triggers ERK-mediated down-regulation.
- ERK activation by gonadotropins is a key mechanism modulating gonadotropin-induced steroidogenesis.
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