Endocrinology, Vol 136, 4382-4389, Copyright © 1995 by Endocrine Society

ARTICLES

Regulation of inhibin/activin subunit messenger ribonucleic acids (mRNAs) by activin A and expression of activin receptor mRNAs in cultured human granulosa-luteal cells

M Eramaa, K Hilden, T Tuuri and O Ritvos
Department of Bacteriology and Immunology, University of Helsinki, Finland.

Recent studies have indicated that activin and inhibin may act as local regulators of cell growth and steroidogenesis in the human ovary. We studied the effect of recombinant human activin A and purified bovine inhibin A on the steady state messenger RNA (mRNA) levels of the inhibin/activin alpha-, beta A-, and beta B-subunits in cultured granulosa-luteal (GL) cells from preovulatory ovarian follicles of women undergoing in vitro fertilization. Activin A induced the expression of a 4.8-kilobase beta B-subunit mRNA transcript without affecting basal expression levels of the alpha- and beta A-subunit mRNAs. It stimulated beta B-subunit mRNA levels in a concentration- and time-dependent manner. Maximal stimulation of beta B-subunit mRNA levels was obtained with 30-100 ng/ml activin A. The level of beta B- subunit mRNAs increased significantly 8 h after stimulation, rising gradually thereafter to a maximum at 48 h. Inhibin A did not affect the mRNA levels of any inhibin/activin subunits, nor did it inhibit the effect of activin A. Recombinant human follistatin did not affect basal beta B-subunit mRNA levels, but it neutralized the effect of activin A. Although hCG induces inhibin/activin alpha- and beta A-subunit mRNA levels in human GL cells, it did not increase basal beta B-subunit levels. By contrast, it inhibited activin A-induced beta B-subunit mRNA levels. On the other hand, activin A decreased hCG-induced mRNA levels of the inhibin alpha-subunit and cytochrome P450 side-chain cleavage (P450scc) enzyme, an important rate-limiting enzyme in human GL cell progestin synthesis. Moreover, we observed by Northern blot analysis that cultured human GL cells as well as freshly isolated preovulatory granulosa cells express the specific mRNAs for all currently known serine/threonine kinase activin receptors, i.e. activin receptors I, IB, II, and IIB. Our results suggest that in GL cells, activin A may locally stimulate synthesis of the beta B-subunit in an autocrine or paracrine manner, and that in human ovary, regulation of the beta B- subunit differs from that of the alpha- and beta A-subunits.

This article has been cited by other articles:

				S. L Al-Musawi, R. T Gladwell, and P. G Knight Bone morphogenetic protein-6 enhances gonadotrophin-dependent progesterone and inhibin secretion and expression of mRNA transcripts encoding gonadotrophin receptors and inhibin/activin subunits in chicken granulosa cells Reproduction, August 1, 2007; 134(2): 293 - 306. [Abstract] [Full Text] [PDF]

				S. Perlman, T. Bouquin, B. van den Hazel, T.H. Jensen, H.T. Schambye, S. Knudsen, and J.S. Okkels Transcriptome analysis of FSH and FSH variant stimulation in granulosa cells from IVM patients reveals novel regulated genes Mol. Hum. Reprod., March 1, 2006; 12(3): 135 - 144. [Abstract] [Full Text] [PDF]

				S. Luisi, P. Florio, F. M. Reis, and F. Petraglia Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy Hum. Reprod. Update, March 1, 2005; 11(2): 123 - 135. [Abstract] [Full Text] [PDF]

				N. Kaivo-Oja, D. G. Mottershead, S. Mazerbourg, S. Myllymaa, S. Duprat, R. B. Gilchrist, N. P. Groome, A. J. Hsueh, and O. Ritvos Adenoviral Gene Transfer Allows Smad-Responsive Gene Promoter Analyses and Delineation of Type I Receptor Usage of Transforming Growth Factor-{beta} Family Ligands in Cultured Human Granulosa Luteal Cells J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 271 - 278. [Abstract] [Full Text] [PDF]

				J. Liu, T. Kuulasmaa, V.-M. Kosma, R. Butzow, T. Vanttinen, C. Hyden-Granskog, and R. Voutilainen Expression of Betaglycan, an Inhibin Coreceptor, in Normal Human Ovaries and Ovarian Sex Cord-Stromal Tumors and Its Regulation in Cultured Human Granulosa-Luteal Cells J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 5002 - 5008. [Abstract] [Full Text] [PDF]

				K. D. Carpenter, K. Hayashi, and T. E. Spencer Ovarian Regulation of Endometrial Gland Morphogenesis and Activin-Follistatin System in the Neonatal Ovine Uterus Biol Reprod, September 1, 2003; 69(3): 851 - 860. [Abstract] [Full Text] [PDF]

				C. Mukasa, M. Nomura, T. Tanaka, K. Tanaka, Y. Nishi, T. Okabe, K. Goto, T. Yanase, and H. Nawata Activin Signaling through Type IB Activin Receptor Stimulates Aromatase Activity in the Ovarian Granulosa Cell-Like Human Granulosa (KGN) Cells Endocrinology, April 1, 2003; 144(4): 1603 - 1611. [Abstract] [Full Text] [PDF]

				N. Kaivo-Oja, J. Bondestam, M. Kamarainen, J. Koskimies, U. Vitt, M. Cranfield, K. Vuojolainen, J. P. Kallio, V. M. Olkkonen, M. Hayashi, et al. Growth Differentiation Factor-9 Induces Smad2 Activation and Inhibin B Production in Cultured Human Granulosa-Luteal Cells J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 755 - 762. [Abstract] [Full Text] [PDF]

				Y. Wang and W. Ge Involvement of Cyclic Adenosine 3',5'-Monophosphate in the Differential Regulation of Activin {beta}A and {beta}B Expression by Gonadotropin in the Zebrafish Ovarian Follicle Cells Endocrinology, February 1, 2003; 144(2): 491 - 499. [Abstract] [Full Text] [PDF]

				J.-S. Roh, J. Bondestam, S. Mazerbourg, N. Kaivo-Oja, N. Groome, O. Ritvos, and A. J. W. Hsueh Growth Differentiation Factor-9 Stimulates Inhibin Production and Activates Smad2 in Cultured Rat Granulosa Cells Endocrinology, January 1, 2003; 144(1): 172 - 178. [Abstract] [Full Text] [PDF]

				J. Liu, T. Vanttinen, C. Hyden-Granskog, and R. Voutilainen Regulation of follistatin-related gene (FLRG) expression by protein kinase C and prostaglandin E2 in cultured granulosa-luteal cells Mol. Hum. Reprod., November 1, 2002; 8(11): 992 - 997. [Abstract] [Full Text] [PDF]

				C. Welt, Y. Sidis, H. Keutmann, and A. Schneyer Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium Experimental Biology and Medicine, October 1, 2002; 227(9): 724 - 752. [Abstract] [Full Text] [PDF]

				A. E. Drummond, M. T. Le, J.-F. Ethier, M. Dyson, and J. K. Findlay Expression and Localization of Activin Receptors, Smads, and {beta}glycan to the Postnatal Rat Ovary Endocrinology, April 1, 2002; 143(4): 1423 - 1433. [Abstract] [Full Text] [PDF]

				R. Jaatinen, J. Bondestam, T. Raivio, K. Hilden, L. Dunkel, N. Groome, and O. Ritvos Activation of the Bone Morphogenetic Protein Signaling Pathway Induces Inhibin {beta}B-Subunit mRNA and Secreted Inhibin B Levels in Cultured Human Granulosa-Luteal Cells J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1254 - 1261. [Abstract] [Full Text] [PDF]

				M. Fawzy, R.F. Harrison, P.G. Knight, N. Groome, A. Anderson, W.R. Robertson, and A. Lambert The effect of gonadotrophins with differing LH/FSH ratios on the secretion of the various species of inhibin in women receiving IVF Hum. Reprod., June 1, 2001; 16(6): 1092 - 1097. [Abstract] [Full Text] [PDF]

				K.-C. Choi, S. K. Kang, C.-J. Tai, N. Auersperg, and P. C. K. Leung The Regulation of Apoptosis by Activin and Transforming Growth Factor-{beta} in Early Neoplastic and Tumorigenic Ovarian Surface Epithelium J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2125 - 2135. [Abstract] [Full Text]

				N. Auersperg, A. S. T. Wong, K.-C. Choi, S. K. Kang, and P. C. K. Leung Ovarian Surface Epithelium: Biology, Endocrinology, and Pathology Endocr. Rev., April 1, 2001; 22(2): 255 - 288. [Abstract] [Full Text]

				J. Liu, C. Hyden-Granskog, and R. Voutilainen Gonadotrophins inhibit and activin induces expression of inhibin/activin {beta}B subunit mRNA in cultured human granulosa-luteal cells Mol. Hum. Reprod., April 1, 2001; 7(4): 319 - 323. [Abstract] [Full Text] [PDF]

				C. K. Welt and A. L. Schneyer Differential Regulation of Inhibin B and Inhibin A by Follicle-Stimulating Hormone and Local Growth Factors in Human Granulosa Cells from Small Antral Follicles J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 330 - 336. [Abstract] [Full Text]

				G. M. Lanuza, N. P. Groome, J. L. Barañao, and S. Campo Dimeric Inhibin A and B Production Are Differentially Regulated by Hormones and Local Factors in Rat Granulosa Cells Endocrinology, June 1, 1999; 140(6): 2549 - 2554. [Abstract] [Full Text]

				R. Li, D. M. Phillips, A. Moore, and J. P. Mather Follicle-Stimulating Hormone Induces Terminal Differentiation in a Predifferentiated Rat Granulosa Cell Line (ROG) Endocrinology, July 1, 1997; 138(7): 2648 - 2657. [Abstract] [Full Text] [PDF]