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Hum. Reprod. Advance Access originally published online on October 3, 2008
Human Reproduction 2009 24(1):176-184; doi:10.1093/humrep/den359
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EGF-like growth factors as LH mediators in the human corpus luteum

I. Ben-Ami1,2,3, L. Armon1, S. Freimann1, D. Strassburger2, R. Ron-El2 and A. Amsterdam1

1 Department of Molecular Cell Biology, the Weizmann Institute of Science, Rehovot, Israel 2 IVF and Fertility Unit, Assaf Harofeh Medical Centre, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

3 Correspondence address. Department of Obstetrics and Gynecology, Assaf Harofeh Medical Centre, Zerifin 70300, Israel. E-mail: idorit{at}netvision.net.il

BACKGROUND: This study aims to investigate the role of epidermal growth factor-like ligands, amphiregulin (Ar) and epiregulin (Ep), in regulation of apoptosis in luteinized human granulosa cells.

METHODS: Luteinized human granulosa cells were obtained from women undergoing IVF treatment. Ar and Ep mRNA levels were measured by real-time RT–PCR. The rate of apoptosis was measured by TUNEL. Progesterone levels were measured using radioimmunoassay. Ar- and Ep-induced activation of signaling cascades and Ar protein levels were detected by western blotting.

RESULTS: LH stimulation of luteinized human granulosa cells induced biosynthesis of Ar and Ep mRNA in a time-dependent manner. The blockade of MEK (by U0126) reduced the expression of LH-induced Ar and Ep biosynthesis. Incubation of the cells with Ar and Ep completely abolished the increase in apoptosis rate induced by serum starvation, and concomitantly caused a pronounced increase in progesterone production. Stimulation of the cells with Ar and Ep also activated the ERK and AKT signaling cascades. Finally, we demonstrated that the pro-survival effect of Ar and Ep is partially dependent on their ability to induce progesterone production.

CONCLUSIONS: Ar and Ep serve as pro-survival LH mediators in the human corpus luteum.

Key words: amphiregulin/epiregulin/luteinized granulosa cells/apoptosis/corpus luteum

Submitted on July 16, 2008; resubmitted on September 6, 2008; accepted on September 10, 2008.


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