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Title: Paracrine and autocrine regulation of epidermal growth factor-like factors in cumulus oocyte complexes and granulosa cells: Key roles for prostaglandin synthase 2 and progesterone receptor
Authors: Shimada, Masayuki
Hernandez-Gonzalez, Inmaculada 
Gonzalez-Robayna, Ignacio 
Richards, JoAnne S.
Keywords: Follicle-Stimulating-Hormone
Ribonucleic-Acid Expression
Endoperoxide Synthase-2
Mice Lacking, et al
Issue Date: 2006
Publisher: 0888-8809
Journal: Molecular Endocrinology 
Abstract: The molecular bridges that link the LH surge with functional changes in cumulus cells that possess few LH receptors are being unraveled. Herein we document that epidermal growth factor ( EGF)- like factors amphiregulin ( Areg), epiregulin ( Ereg), and betacellulin ( Btc) are induced in cumulus oocyte complexes ( COCs) by autocrine and paracrine mechanisms that involve the actions of prostaglandins ( PGs) and progesterone receptor ( PGR). Areg and Ereg mRNA and protein levels were reduced significantly in COCs and ovaries collected from prostaglandin synthase 2 ( Ptgs2) null mice and Pgr null ( PRKO) mice at 4 h and 8 h after human chorionic gonadotropin, respectively. In cultured COCs, FSH/forskolin induced Areg mRNA within 0.5 h that peaked at 4 h, a process blocked by inhibitors of p38MAPK ( SB203580), MAPK kinase (MEK) 1 ( PD98059), and PTGS2 ( NS398) but not protein kinase A ( PKA) ( KT5720). Conversely, AREG but not FSH induced Ptsg2 mRNA at 0.5 h with peak expression of Ptgs2 and Areg mRNAs at 4 h, processes blocked by the EGF receptor tyrosine kinase inhibitor AG1478 ( AG), PD98059, and NS398. PGE2 reversed the inhibitory effects of AG on AREG-induced expression of Areg but not Ptgs2, placing Ptgs2 downstream of EGF-R signaling. Phorbol 12- myristate 13-acetate (PMA) and adenovirally expressed PGRA synergistically induced Areg mRNA in granulosa cells. In COCs, AREG not only induced genes that impact matrix formation but also genes involved in steroidogenesis ( StAR, Cyp11a1) and immune cell-like functions (Pdcd1, Runx1, Cd52). Collectively, FSH-mediated induction of Areg mRNA via p38MAPK precedes AREG induction of Ptgs2 mRNA via ERK1/2. PGs acting via PTGER2 in cumulus cells provide a secondary, autocrine pathway to regulate expression of Areg in COCs showing critical functional links between G protein- coupled receptor and growth factor receptor pathways in ovulating follicles.
ISSN: 0888-8809
DOI: 10.1210/me.2005-0504
Source: Molecular Endocrinology[ISSN 0888-8809],v. 20 (6), p. 1352-1365
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