Biosynthesis and Secretion of Follicle-Stimulating Hormone*

Chappel, Scott C.; Ulloa‐Aguirre, Alfredo; Coutifaris, Christos

doi:10.1210/edrv-4-2-179

Cited by 251 publications

(89 citation statements)

References 132 publications

(268 reference statements)

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“…The 38-kDa species corresponds in size to the species detected in both the oFSH and rbFSH standards. Some microheterogeneity in the post-translational modifications of the FSH may explain the broad bands observed (see chromatofocusing results) (32,33 I), reflecting that the antiserum was raised against oFSH rather than bESH.…”

Section: Resultsmentioning

confidence: 97%

Expression of biologically active heterodimeric bovine follicle-stimulating hormone in milk of transgenic mice.

Greenberg

Anderson²,

Hsueh³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Follicle-stimulating hormone (FSH; follitropin) is a pituitary glycoprotein composed of two posttranslationally modified subunits, which must properly assemble to be biologically active. FSH has been difficult to purify and to obtain in quantities sufficient for detailed biochemical studies. We have targeted FSH expression to the mammary gland of transgenic mice by using cDNAs encoding the bovine a and FSHP subunits and a modified rat f-casein gene-based expression system. Lines of bigenic mice expressing both subunits have been generated either by coinection of the subunit transgenes or by mating mice that acquired and expressed transgenes encoding an individual subunit. Up to 60 international units (15 ,sg) of biologically active FSH per ml was detected in the milk of the bigenic mice. These lines provide a model system for studying the post-transcriptional mechanisms that effect the expression and secretion of this heterodimeric hormone.Follicle-stimulating hormone (FSH; follitropin) is a member of the glycoprotein family of pituitary hormones, which includes thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and chorionic gonadotropin (CG). Like LH and CG, FSH is a gonadotropin and is composed of a common a subunit that is noncovalently linked to a hormone-specific P subunit (1, 2). FSH has been difficult to purify and to obtain in sufficient quantities for detailed biochemical studies (for a review, see ref. 3). The a and FSHI subunits are posttranslationally modified, and the nature and extent of such modifications can exert a profound effect on subunit assembly, secretion, and stability (4-6). Only heterodimers with appropriately glycosylated subunits exhibit significant biological and receptor-binding activity (5,7,8). Targeting FSH to the mammary gland of transgenic animals would, therefore, serve as a model system in which to study glycoprotein processing and secretion as well as a means to produce large quantities of FSH. A standardized source of recombinant FSH would be useful to both human and livestock fertilization programs to achieve the reproducible development of ovarian follicles.Several different milk protein-based constructs have been employed to express diverse heterologous proteins in the milk of a variety of transgenic animals (for reviews, see refs. 9-11). We have demonstrated previously that a -524/+490 minimal rat f3-casein promoter fragment can direct the expression of chloramphenicol acetyltransferase to the mammary gland (12). To determine whether the mammary gland could be used to secrete large quantities of a bioactive heterodimeric protein into milk, we have used a modified rat ,8-casein-based vector to target and express bovine FSH (bFSH) to the mammary gland and into the milk of transgenic mice. MATERIALS AND METHODSConstruction of the Transgenes. The FSH subunit cDNAs were obtained from Genzyme; a as a 730-base-pair (bp) EcoRI fragment and FSH(3 as a 560-bp EcoRI/BamHI fragment. The cDNA fragments were inserted into pUC19 (13) with the rat 13-casein -524/+49...

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Section: Resultsmentioning

confidence: 97%

Expression of biologically active heterodimeric bovine follicle-stimulating hormone in milk of transgenic mice.

Greenberg

Anderson²,

Hsueh³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…The main difference among the various isoforms is caused by charge, which in FSH is mainly determined by its content in terminal sialic acid residues (Chappel et al 1983, Baenzinger & Green 1988, Ulloa-Aguirre et al 1995, although differences in nonterminal carbohydrates also play an important role in determining the heterogenous nature of the several members of the glycoprotein hormone family (Ulloa-Aguirre et al 1988b, Papandreou et al 1993, Creus et al 1996. We and others have found that the receptor binding activity of the intrapituitary FSH isoforms varies depending on the charge of the isoform (Stanton et al 1992, Ulloa-Aguirre et al 1992, Yding Andersen et al 1999.…”

Section: Discussionmentioning

confidence: 99%

“…The pituitary gonadotrophin follicle-stimulating hormone (FSH) regulates the development and maintenance of several basic reproductive processes, including gametogenesis, follicular maturation and ovulation (Chappel et al 1983). This gonadotrophin is a member of a glycoprotein hormone family that includes luteinizing hormone (LH), thyroid-stimulating hormone (TSH) and choriogonadotrophin and consists of a common -subunit and a unique -subunit (Pierce et al 1971, Boothby et al 1981, Pierce & Parsons 1981.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of the charge variants of human follicle-stimulating hormone

Timossi¹,

Barrios-De-Tomasi²,

González-Suárez³

et al. 2000

Journal of Endocrinology

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FSH is synthesized and secreted by the anterior pituitary gland in multiple molecular forms; the release of these isoforms depends on the endocrine status of the donor at the time of sample collection. In the present study, we analysed the possibility that the FSH charge isoforms may exert differential effects at the target cell. Seven FSH isoform mixes were isolated from pooled anterior pituitary glycoprotein extracts by high resolution chromatofocusing, followed by affinity chromatography, which removed nearly 90% of the LH that co-eluted with the FSH isoforms during chromatofocusing. The isoforms (isoform I, pH >7·10; II, pH range 6·60-6·20; III, pH 5·47-5·10; IV, pH 5·03-4·60; V, pH 4·76-4·12; VI, pH 4·05-3·82 and VII, pH <3·80) were then tested for their capacity to stimulate cAMP release, androgen aromatization and tissue-type plasminogen activator (tPA) enzyme activity and cytochrome P450 aromatase, tPA and inhibin -subunit mRNA production by rat granulosa cells in culture. cAMP and oestradiol production were determined by RIA, tPA enzyme activity by SDS-PAGE and zymography and all mRNAs by northern blot hybridization analysis and semiquantitative RT-PCR. All isoforms, with the exception of isoform I, stimulated synthesis and release of cAMP, oestrogen and tPA enzyme activity in a dosedependent manner; the potency of the less acidic isoforms (pH 6·60-4·60) was greater than that exhibited by the more acidic/sialylated analogs (pH 4·76 to <3·80; potencies II>III>IV>V>VII>VI). A similar trend was observed in terms of cytochrome P450 aromatase and tPA mRNA production. In contrast, when FSH-stimulated production of -inhibin mRNA was analysed, isoforms V-VII were significantly more potent (two-to threefold) than the less acidic/sialylated counterparts (II-IV). In contrast to isoforms II-VII (which behaved as FSH agonists), isoform I (elution pH >7·10) completely blocked P450 aromatase and tPA mRNA expression, without altering that of a constitutively expressed gene (glyceraldehyde-3-phosphate dehydrogenase). These results show for the first time that the naturally occurring human FSH isoforms may exhibit differential or even unique effects at the target cell level.

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“…In other mammals, a pattern of glycosylation of FSH that differs from that of LH has been described [15]. It is because of this difference in glycosylation patterns that LH is eliminated from the circulation faster than FSH [16].…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of the secretion of luteinizing hormone and follicle-stimulating hormone around the time of ovulation in the bitch

Gier

Kooistra

Djajadiningrat-Laanen

et al. 2006

Theriogenology

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Plasma concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were determined 3-6 times daily in six Beagle bitches from the start of the follicular phase until 5 d after the estimated day of ovulation. The aim of the study was to gain more detailed information regarding the changes in and the temporal relation between these hormones around the time of ovulation. In all bitches, the pre-ovulatory LH surge was accompanied by a pre-ovulatory FSH surge. The mean duration of the preovulatory FSH surge (110 AE 8 h) was significantly longer than that of the pre-ovulatory LH surge (36 AE 5 h). The FSH surge started concomitantly with the pre-ovulatory LH surge in four bitches, and 12 h before the start of the LH surge in the other two bitches. The pre-ovulatory LH surge had a bifurcated pattern in four bitches. The mean plasma LH concentration before (1.9 AE 0.4 mg/L) and after (1.9 AE 0.3 mg/L) the pre-ovulatory LH surge were similar. The mean plasma FSH concentration during the period 72-28 h before the pre-ovulatory LH surge (1.6 AE 0.3 U/L) was lower (P < 0.001) than that during the period 100-144 h after the preovulatory LH surge (3.1 AE 0.2 U/L). In conclusion, this study demonstrated concurrent pre-ovulatory surges of FSH and LH and provided more evidence for differential regulation of the secretion of FSH and LH. #

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Biosynthesis and Secretion of Follicle-Stimulating Hormone*

Cited by 251 publications

References 132 publications

Expression of biologically active heterodimeric bovine follicle-stimulating hormone in milk of transgenic mice.

Expression of biologically active heterodimeric bovine follicle-stimulating hormone in milk of transgenic mice.

Differential effects of the charge variants of human follicle-stimulating hormone

Differential regulation of the secretion of luteinizing hormone and follicle-stimulating hormone around the time of ovulation in the bitch

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