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Query: UNIPROT:P06889 (Mol)
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Growth factors are known to regulate ovarian function. In the present study, effects of these growth factors, TGF-alpha, TGF-beta, and activin-A were tested on spontaneous porcine oocyte maturation. Cumulus-oocyte complexes (COC) were cultured in the presence of TGF-alpha, TGF-beta, and activin-A for 48 hr. Stages of meiotic maturation were assessed by staining with acetic orcein. Among these factors, only TGF-alpha significantly enhanced the maturation rate, whereas TGF-beta suppressed the spontaneous maturation rate. The site of action of TGF-alpha on COC and the interaction between TGF-alpha and EGF receptor was also examined. Denuded oocytes, alone or in coculture with cumulus cells, were cultured in the presence of TGF-alpha for 48 hr. TGF-alpha did not have any significant effect on denuded oocyte maturation. Heptanol was employed to investigate the role of gap junctions on TGF-alpha-induced oocyte maturation in COC. Although heptanol did not have any significant effect in the control medium, heptanol reversed the stimulatory effect of TGF-alpha on porcine oocyte maturation. TGF-alpha was able to displace 125I-EGF binding on COC. In conclusion, TGF-alpha enhances the spontaneous maturation of porcine oocytes by generating positive signal(s) in cumulus cells that are transferred to the oocyte via gap junctions. TGF-alpha shares the same receptor with EGF on porcine COC. TGF-beta, in contrast, inhibits porcine oocyte maturation.
Mol Reprod Dev 1994 Jun
PMID:Effects of transforming growth factors and activin-A on in vitro porcine oocyte maturation. 808 Jun 44

The paracrine actions of bovine follistatin (FS), human recombinant activin A and bovine inhibin on progesterone (P), androstenedione (A4) and inhibin production, were investigated using LH-stimulated immature bovine thecal cells. The presence of FS (3-100 ng/ml) alone caused a dose-dependent stimulation of P production by thecal cells induced by bovine LH (10 ng/ml). The stimulatory effect of FS on P production at 10 or 30 ng/ml was reversed to control levels with the addition of activin (10 or 30 ng/ml). Treatment with FS did not significantly effect on A4 production. Activin alone had no consistent effect on A4 production (measured using two different antibodies), but had a dose-dependent inhibitory effect on P production. Treatments of cells with inhibin had no significant effect on the LH-induced production of either P or A4. Testosterone production in FS; activin- or inhibin-treated cells was not different from controls. Northern analysis showed that inhibin beta subunit was not detected in thecal mRNA, whereas there were very faint bands of inhibin alpha subunit and FS which were attributed to contamination of granulosa cells (GC). We conclude that FS in vitro has a stimulatory effect on P production by bovine thecal cells, and that activin has the ability to reverse the stimulatory effect of P production. Unlike the rat and human thecal cells, activin and inhibin had no significant effect on LH-induced androgen synthesis by bovine thecal cells. We propose that FS secreted by the GC acts as a paracrine modulator upon thecal cells to directly stimulate the production of P independently of activin.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1993 Nov
PMID:The effects of follistatin, activin and inhibin on steroidogenesis by bovine thecal cells. 814 2

Transforming growth factor beta (TGF-beta) and activin bind to receptor complexes that contain two distantly related transmembrane serine/threonine kinases known as receptor types I and II. The type II receptors determine ligand binding specificity, and each interacts with a distinct repertoire of type I receptors. Here we identify a new type I receptor for activin, ActR-IB, whose kinase domain is nearly identical to that of the recently cloned TGF-beta type I receptor, T beta R-I. ActR-IB has the structural and binding properties of a type I receptor: it binds activin only in the presence of an activin type II receptor and forms a heteromeric noncovalent complex with activin type II receptors. In Mv1Lu lung epithelial cells, ActR-IB and T beta R-I signal a common set of growth-inhibitory and transcriptional responses in association with their corresponding ligands and type II receptors. The transcriptional responses include elevated expression of fibronectin and plasminogen activator inhibitor 1. Although T beta R-I and ActR-IB are nearly identical in their kinase domains (90% amino acid sequence identity), their corresponding type II receptor kinase domains are very different from each other (42% amino acid sequence identity). Therefore, signaling of a specific set of responses by TGF-beta and activin correlates with the presence of similar type I kinases in their complex. Indeed, other TGF-beta and activin type I receptors (TSR-I and ActR-I) whose kinase domains significantly diverge from those of T beta R-I and ActR-IB do not substitute as mediators of these growth-inhibitory and extracellular matrix transcriptional responses. Hence, we conclude that the type I receptor subunits are primary specifiers of signals sent by TGF-beta and activin receptor complexes.
Mol Cell Biol 1994 Jun
PMID:Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin. 819 24

The type II receptors for the polypeptide growth factors transforming growth factor beta (TGF-beta) and activin belong to a new family of predicted serine/threonine protein kinases. In Xenopus embryos, the biological effects of activin and TGF-beta 1 are strikingly different; activin induces a full range of mesodermal cell types in the animal cap assay, while TGF-beta 1 has no effects, presumably because of the lack of functional TGF-beta receptors. In order to assess the biological activities of exogenously added TGF-beta 1, RNA encoding the TGF-beta type II receptor was introduced into Xenopus embryos. In animal caps from these embryos, TGF-beta 1 and activin show similar potencies for induction of mesoderm-specific mRNAs, and both elicit the same types of mesodermal tissues. In addition, the response of animal caps to TGF-beta 1, as well as to activin, is blocked by a dominant inhibitory ras mutant, p21(Asn-17)Ha-ras. These results indicate that the activin and TGF-beta type II receptors can couple to similar signalling pathways and that the biological specificities of these growth factors lie in their different ligand-binding domains and in different competences of the responding cells.
Mol Cell Biol 1994 Jun
PMID:The transforming growth factor beta type II receptor can replace the activin type II receptor in inducing mesoderm. 819 64

A transmembrane protein serine/threonine kinase, Atr-I, that is structurally related to receptors for members of the transforming growth factor-beta (TGF-beta) family has been cloned from Drosophila melanogaster. The spacing of extracellular cysteines and the cytoplasmic domain of Atr-I resemble most closely those of the recently described mammalian type I receptors for TGF-beta and activin. When expressed alone in test cells, Atr-I is unable to bind TGF-beta, activin, or bone morphogenetic protein 2. However, Atr-I binds activin efficiently when coexpressed with the distantly related Drosophila activin receptor Atr-II, with which it forms a heteromeric complex. Atr-I can also bind activin in concert with mammalian activin type II receptors. Two alternative forms of Atr-I have been identified that differ in an ectodomain region encompassing the cysteine box motif characteristic of receptors in this family. Comparison of Atr-I with other type I receptors reveals the presence of a characteristic 30-amino-acid domain immediately upstream of the kinase region in all these receptors. This domain, of unknown function, contains a repeated Gly-Ser sequence and is therefore referred to as the GS domain. Maternal Atr-I transcripts are abundant in the oocyte and widespread during embryo development and in the imaginal discs of the larva. The structural properties, binding specificity, and dependence on type II receptors define Atr-I as an activin type I receptor from D. melanogaster. These results indicate that the heteromeric kinase structure is a general feature of this receptor family.
Mol Cell Biol 1994 Feb
PMID:Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex. 828 34

We studied the expression of inhibin/activin subunit mRNAs in granulosa-luteal cells of preovulatory ovarian follicles obtained from women undergoing in vitro fertilization, and in corpus luteum tissue samples of early pregnancy. Northern analysis of granulosa-luteal cell and corpus luteum RNA with single-stranded cDNA or cRNA probes revealed an 1.6-kb mRNA for the alpha subunit and about 6.0-, 4.0-, 2.8-, and 1.7-kb transcripts for the beta A subunit. No clear hybridization signal for the beta B subunit could be detected. The relative expression levels of alpha and beta A subunit mRNAs were determined at 2-day intervals in granulosa-luteal cells cultured for 5 to 11 days. The levels of alpha subunit mRNAs declined steadily with increasing culture age, whereas those of beta A remained unchanged. Reverse transcription-polymerase chain reaction analysis with 35 amplification cycles confirmed the expression of alpha and beta A subunit mRNAs in cultured granulosa-luteal cells. The beta B transcripts were also weakly detectable by this sensitive assay. In situ hybridization of human early pregnancy corpus luteum revealed intense hybridization with the alpha cRNA probe and a weaker signal for the beta A subunit in the granulosa cell compartment. We conclude that: (1) the inhibin alpha and beta A subunits (and to a lesser extent beta B) are expressed in cultured human granulosa-luteal cells; (2) during extended culture periods the alpha/beta A mRNA expression ratio decreases; and that (3) the alpha and beta A subunit mRNA expression is observed in the granulosa cell compartment of early pregnancy corpora lutea.
Mol Cell Endocrinol 1993 Apr
PMID:Inhibin/activin subunit mRNA expression in human granulosa-luteal cells. 831 22

Localization of inhibin/activin subunit mRNAs within the macaque ovary from the immediate pre-ovulatory period of the menstrual cycle, when serum immunoreactive inhibin begins to rise, to day 9 of the luteal phase, when serum inhibin concentrations are maximal, was investigated using in-situ hybridization. Ovaries were studied on the day of the LH surge (day 0) and on days 2, 5, and 9 of the luteal phase by hybridizing frozen tissue sections with radiolabelled riboprobes specific to the inhibin/activin alpha-, beta A- and beta B-subunits. After autoradiographic exposure for 10 and 21 days, grain concentrations were quantified by image analysis. Moderate expression of alpha-, beta A- and beta B-subunit mRNA was present within the granulosa cells of the pre-ovulatory follicle (day 0). The granulosa-lutein cells of the corpora lutea expressed high levels of alpha-subunit at days 2, 5 and 9. mRNAs for beta A and beta B were detected at low but significant levels in all of the corpora lutea. All healthy antral follicles exhibited a high level of expression of beta B-subunit mRNA in the granulosa cells. On day 2 after ovulation these follicles also expressed high alpha- and moderate beta A-subunit mRNA. On day 9 the beta B-inhibin mRNA in antral follicles was found in association with low expression of the other subunits. Small follicles in ovaries on day 2 expressed moderate alpha- and low levels of beta B-subunit mRNA, while mRNA for beta A was absent. alpha-subunit mRNA expression was present on day 5 while neither beta A- nor beta B-subunit mRNA was detected. On day 9 a proportion of small follicles expressed alpha- and beta A-subunit mRNA. These results demonstrate that marked differences are present in the levels of expression of the three inhibin/activin subunit genes between follicles and the corpus luteum. The predominance of the beta B-subunit mRNA within antral follicles would be consistent with the synthesis of activin. The predominance of the alpha-subunit combined with the low expression of the beta-subunits in the corpus luteum suggests that both biologically active inhibin and free alpha-subunit are produced by the primate corpus luteum.
J Mol Endocrinol 1993 Jun
PMID:Localization of inhibin/activin subunit mRNAs during the luteal phase in the primate ovary. 837 10

The expression of genes encoding inhibin/activin subunits and activin receptor was examined in four cultured Leydig tumor cells (MA-10, I-10, R2C, and LC-540). Inhibin alpha-subunit gene was highly expressed in Leydig tumor cell lines except LC-540. Both inhibin beta-A- and beta-B-subunit mRNAs were present in low levels. The 6.5-kb beta-A-subunit mRNA was detected in MA-10, R2C and LC-540 cells, and not in I-10 cells. The expression of the two species of beta-B-subunit mRNA is cell specific. In MA-10 and I-10 cells, 4.4-kb beta-B-subunit mRNA was the predominant species, while in R2C and LC-540 cells both 4.4-kb and 3.3-kb mRNA were present in equal quantities. By contrast, two species (6 and 3 kb) of activin receptor ActRII mRNA were identified in equal intensity in all four Leydig tumor cell lines. Addition of cAMP derivative to MA-10 cells at 0.1 mM for 17 h or 1 mM for 5 h produced a two-fold increase in inhibin alpha-subunit mRNA levels, and small or no significant change in inhibin beta-B-subunit and ActRII mRNAs. However, a 70-80% reduction in inhibin beta-A-subunit mRNA was observed by 1 mM cAMP for 5 h. We concluded that: (1) the inhibin/activin subunit genes and activin receptor gene are co-expressed in Leydig tumor cell lines, and (2) the three inhibin/activin subunit genes are expressed differently, while the activin receptor gene is expressed identically in the four cell lines.
Mol Cell Endocrinol 1993 Jul
PMID:Inhibin/activin subunits and activin receptor are co-expressed in Leydig tumor cells. 839 20

Follistatin was originally identified as a specific inhibitor of follicle stimulating hormone secretion and later characterized as a binding protein for activin. Since activin regulates hormone secretion and cell differentiation, the importance of understanding the mechanisms regulating the synthesis of its binding protein, follistatin, is evident. To study the regulation of follistatin gene expression, we first determined the transcription start site (cap site) of the rat follistatin gene using primer extension and ribonuclease protection assay. Our results led to the identification of multiple cap sites located at three different positions of the promoter. DNA sequence analysis revealed that each cap site was located at approximately 30 nucleotide (nt) downstream of three distinct TATA-like sequences. In primary cultures of rat granulosa cells, transfection studies using 5'-flanking regions of follistatin gene fused to the chloramphenicol acetyltransferase (CAT) reporter gene revealed the presence of two DNA segments that act to suppress basal transcriptional activity. The promoter activity of the CAT construct containing 2.6 kilo base pairs (kb) of 5'-flanking region was induced 2.5-fold above basal activity by forskolin (10 microM), and 1.6-fold by 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 nM). Co-treatment with forskolin and TPA resulted in a 6.4-fold induction in its promoter activity, suggesting that two distinct signal transduction pathways, the cAMP-dependent protein kinase-A pathway and diacylglycerol-dependent protein kinase-C pathway, act coordinately to modulate follistatin gene transcription. Experiments using a series of 5'-flanking region deletion constructs located the regulatory regions responsive to these two pharmacological agents at nt -312 to -32 and -35 to +139.
Mol Cell Endocrinol 1993 Mar
PMID:Structural and functional characterization of the rat follistatin (activin-binding protein) gene promoter. 847 73

Granulosa cells produce inhibin and activin, proteins implicated in the local regulation of preovulatory follicular development. To assess interactions among FSH, LH, inhibin and activin on primate granulosa cell aromatase activity, we studied primary granulosa cell cultures from the ovaries of the common marmoset (Callithrix jacchus), a monkey with an ovarian cycle similar in length to the human cycle. The distinctive action of activin was augmentation of gonadotropin-responsive aromatase activity throughout antral follicular development. FSH-stimulated aromatase activity in granulosa cells from immature follicles was augmented many fold by picomolar amounts of activin. In cell cultures from preovulatory follicles, the presence of activin stimulated basal aromatase activity in the absence of gonadotropin, as well as augmenting the action of LH. Thus, locally produced activin has the potential to modulate aromatase activity in developing ovarian follicles. By contrast, inhibin or inhibin alpha-subunit purified from bovine follicular fluid had minimal effects on aromatase activity. The only significant effect was slight suppression of FSH-inducible aromatase activity in granulosa cells from immature follicles at an inhibin concentration of 100 ng/ml. The finding that inhibin has a negligible effect on aromatase activity in granulosa cells from mature follicles suggests that it is unlikely to exert a physiologically significant influence on aromatase activity in vivo. However, evidence from other studies suggests that inhibin might affect aromatization indirectly through acting locally to modulate thecal androgen (aromatase substate) production. Therefore, both inhibin and activin have the potential to contribute at different levels to paracrine and autocrine regulation of follicular oestrogen synthesis.
J Steroid Biochem Mol Biol 1993 Mar
PMID:Local regulation of primate granulosa cell aromatase activity. 847 57


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