Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Follistatin is a glycosylated single-chain protein originally isolated from porcine follicular fluid. It specifically inhibits the secretion of FSH from the pituitary. We have now isolated and characterized a cDNA for rat follistatin from the PMSG-stimulated ovarian library. The deduced amino acid sequence of the rat follistatin precursor is highly homologous (greater than 98%) to porcine and human follistatins including potential Asn-glycosylation sites. The genomic clone encoding rat follistatin was also isolated and revealed that the exon and intron organization of the follistatin gene structure is conserved among rat, porcine, and human. Northern analyses in rat tissues demonstrated that the follistatin gene is expressed not only in the ovary but also in the kidney and brain. In the immature rat ovary, the follistatin mRNA level is stimulated by PMSG injection (20 IU/rat), but is not affected by human CG (10 IU/rat) after PMSG administration. In situ hybridization studies revealed that the mRNA level in the ovary was low in primordial follicles, but dramatically increased in the granulosa cells of the growing secondary and tertiary follicles and then decreased in the mature preovulatory follicles. A strong follistatin mRNA signal was observed over the collecting tubules of the outer medulla of the kidney, and a weak to moderate signal was detected in brain. The broad tissue distribution of follistatin mRNA strongly suggests other physiological roles for follistatin besides the inhibition of pituitary FSH release.
Mol Endocrinol 1989 Apr
PMID:Follistatin gene expression in the ovary and extragonadal tissues. 272 28

Bacteriophage T5 is not confined by the restriction systems of the second type EcoRII and EcoRV. Bacteriophage T5 DNA is not modified by EcoRII and EcoRV methylases in vivo. The sites of recognition for restriction endonuclease EcoRV are mapped at 24.4; 57.6; 68.5; 70.2% of T5 DNA, while the sites at 5.1; 7.6% are recognized by EcoRII, the sites at 5.75; 6.0 and 6.5% are recognized by HpaI in FST. A high activity of restriction endonucleases EcoRI and EcoRV is demonstrated in crude extracts of E. coli B834 (RI) and E. coli B834 (RV) cells infected by bacteriophage T5. The simultaneous infection of E. coli B834 (RI) or E. coli B834 (RV) cells by the amber mutants of bacteriophage T5 and the suppressing phage lambda NM761 does not result in the protection of lambda DNA by the T5 anti-restriction mechanism. The presented data support the hypothesis that the anti-restriction mechanism of bacteriophage T5 is based on prevention of T5 DNA contacts with restriction enzymes by a specific phage protein.
Mol Gen Mikrobiol Virusol 1987 Jan
PMID:[Various characteristics of the anti-restriction mechanism in bacteriophage T5]. 303 90

Follistatin, a novel, single chain, glycosylated polypeptide bearing no homology with previously characterized inhibins but exhibiting potent and specific pituitary FSH-release inhibition has been structurally characterized by protein microsequencing, cDNA cloning, and DNA sequencing. Two populations of clones differing in their 3'-untranslated sequences were found to encode a 344 amino acid precursor protein and an identical but carboxyl terminal truncated 317 amino acid precursor, respectively. Additionally, one clone, FS18, contained two introns and probably resulted from reverse transcription of heterogeneous nuclear RNA during cDNA library construction. Follistatin is unusually cysteine-rich, containing 36 cysteines in the mature coding sequence of 315 amino acids and an extremely acidic carboxyl terminal region, FS(292-304), comprised of Glu-Asp-Thr-Glu-Glu-Glu-Glu-Glu-Asp-Glu-Asp-Gln-Asp which probably resides outside a tightly cross-linked protein sphere. The heparin-binding ability of follistatin can probably be ascribed to the basic region specified by FS(75-86), Lys-Lys-Cys-Arg-Met-Asn-Lys-Lys-Asn-Lys. Overall, follistatin is organized into three homologous domains, FS(66-135), FS(139-210), and FS(216-287) containing 70, 72, and 72 amino acids, respectively, which show a 52% homology among themselves and a 57% homology with the 56 amino acid human pancreatic secretory trypsin inhibitor protein when aligned for maximum homology.
Mol Endocrinol 1987 Nov
PMID:Structural characterization of follistatin: a novel follicle-stimulating hormone release-inhibiting polypeptide from the gonad. 315 65

The extracellular glycoprotein BM-40 consists of three domains, an acidic domain I, a follistatin (FS)-like domain II and a calcium-binding EC domain with an EF-hand related motif. BM-40 and several other related proteins (QR1, SC1/hevin, testican and tsc-36/FRP) are members of a novel modular protein family that share the FS domain followed by an EC domain. We have expressed this pair of FS and EC domains (mutant delta I) and the calcium-binding EC domain alone (mutant delta I, II) of human BM-40 as recombinant proteins in human 293 cells. Circular dichroism demonstrated that both mutants were obtained as folded proteins with a distinct three-dimensional conformation. In addition, mutant delta I, II could be readily crystallized and diffraction patterns with a resolution limit of 2.4 A resolution were obtained. Calcium binding to this fragment was ten times weaker (Kd = 0.8 microM) than for the wild-type protein. Identical reversible increases in alpha-helicity upon calcium binding were observed for the 150-residue long mutant delta I, II and for BM-40 (286 residues). A 26-residue synthetic peptide corresponding to the EF-hand related motif exhibited much weaker calcium binding. The apparent dissociation constant decreased with increasing peptide concentration (from Kd 2.4 mM at 1 microM, to Kd 0.3 mM at 100 microM peptide concentration) and calcium binding was accompanied by dimerization of the peptide. This suggests that for strong calcium binding the EF-hand related motif has to be embedded into a larger protein domain that can form an autonomously folding protein module. The EC domain was also shown by surface plasmon resonance assay to be responsible for calcium-dependent binding to collagen IV with an affinity (Kd = 19 microM) only sixfold lower than that of intact human BM-40.
J Mol Biol 1995 Oct 20
PMID:The C-terminal portion of BM-40 (SPARC/osteonectin) is an autonomously folding and crystallisable domain that binds calcium and collagen IV. 756 94

The regulation of the follistatin mRNA by hormones and endocrine manipulations was examined in granulosa cell cultures. The follistatin mRNA accumulation was stimulated in a dose-dependent manner by follicle-stimulating hormone (FSH) with a maximal response twice as great as in control cultures at a dose of 100 ng/ml FSH. The time course of the FSH effect on follistatin mRNA had a biphasic effect in which FSH increased follistatin mRNA within 2 h, and subsequently reduced it to below the control level. 8-Br-8 brom-adenosine 3,5-cyclic monophosphate (cAMP) (2 mM) and phorbol 12-myristate 13-acetate (PMA) (10 nm) induced a time-dependent increase in follistatin mRNA levels, with the maximal response at 6 h and 2 h, respectively. Co-treatment of the granulosa cells with cAMP and PMA demonstrated that 0.2 mM of 8-Br-cAMP suppressed the follistatin mRNA of the control and the samples with a small amount of PMA in the granulosa cells. Follistatin expression is therefore regulated by protein kinase A and protein kinase C pathways in rat granulosa cells. A more dramatic stimulation of follistatin mRNA was observed when this culture was treated with activin, and follistatin also blocked the effect of activin on the follistatin mRNA.
Mol Cell Endocrinol 1995 Apr 01
PMID:Regulation of follistatin messenger ribonucleic acid in cultured rat granulosa cells. 766 79

In primary cultures of rat pituitary cells, inhibin and follistatin reduce steady state levels of FSH beta mRNA to less than 10% of control within 4-6 h, while activin increases this mRNA 2- to 3-fold after 2-4 h of treatment. The effects of these three gonadal polypeptide hormones on the LH beta and common alpha-subunit mRNAs are more gradual and of lesser magnitude. The present study was designed to determine whether inhibin, activin, and/or follistatin act at the posttranscriptional level by altering the stability of the gonadotropin subunit mRNAs. To determine the decay rates of FSH beta, LH beta, and alpha-subunit mRNAs, primary pituitary cell cultures were treated for 1-24 h with either of two transcriptional inhibitors, actinomycin-D or 5,6-dichloro-1-beta-ribofuranosyl benzimidazole (DRB), in the presence or absence of recombinant human inhibin-A, recombinant human activin-A, or purified bovine follistatin. The decay of preexisting gonadotropin subunit mRNAs was followed by Northern blot analysis. Levels of LH beta and alpha-subunit mRNAs remained constant or increased during the 24-h exposure to transcriptional inhibitors; therefore, it was not possible to calculate their half-lives. The stability of these mRNAs was not altered by inhibin, activin, or follistatin. In contrast, FSH beta mRNA turned over rapidly: the estimated half-life was 2.6 +/- 0.19 h (mean +/- SEM of eight determinations) after actinomycin-D treatment and 1.9 +/- 0.14 h (mean +/- SEM of 12 determinations) after DRB treatment. When new RNA synthesis was blocked by either actinomycin-D or DRB, there were no significant effects of inhibin, activin, or follistatin on the stability of FSH beta mRNA (n = 2-4 for each hormone). The decay of FSH beta mRNA in the presence of inhibin or follistatin alone, however, was even more rapid than that determined after the administration of transcriptional inhibitors (P < 0.005). After an initial lag of 1-2 h, the half-life of FSH beta mRNA was 0.88 +/- 0.15 h (n = 4) or 0.62 +/- 0.11 h (n = 3), in the presence of inhibin or follistatin, respectively. The most likely interpretation of these results is that inhibin/follistatin reduces steady state levels of FSH beta mRNA by inducing a labile protein that accelerates the degradation of this mRNA species, and the synthesis of this protein is blocked by actinomycin-D or DRB treatment. It is not clear at present whether inhibin, follistatin, and activin have additional effects on transcription of the gonadotropin subunit genes.
Mol Endocrinol 1993 May
PMID:Decay of follicle-stimulating hormone-beta messenger RNA in the presence of transcriptional inhibitors and/or inhibin, activin, or follistatin. 768 52

A combination of behavioural observation, DNA fingerprinting, and allozyme analysis were used to examine natal dispersal in a wild rabbit population. Rabbits lived in territorial, warren based social groups. Over a 6-year period, significantly more male than female rabbits moved to a new social group before the start of their first breeding season. This pattern of female philopatry and male dispersal was reflected in the genetic structure of the population. DNA fingerprint band-sharing coefficients were significantly higher for females within the same group than for females between groups, while this was not the case for males. Wright's inbreeding coefficients were calculated from fingerprint band-sharing values and compared to those obtained from allozyme data. There was little correlation between the relative magnitudes of the F-statistics calculated using the two techniques for comparisons between different social groups. In contrast, two alternative methods for calculating FST from DNA fingerprints gave reasonably concordant values although those based on band-sharing were consistently lower than those calculated by an 'allele' frequency approach. A negative FIS value was obtained from allozyme data. Such excess heterozygosity within social groups is expected even under random mating given the social structure and sex-biased dispersal but it is argued that the possibility of behavioural avoidance of inbreeding should not be discounted in this species. Estimates of genetic differentiation obtained from allozyme and DNA fingerprint data agreed closely with reported estimates for the yellow-bellied marmot, a species with a very similar social structure to the European rabbit.
Mol Ecol 1995 Apr
PMID:Natal dispersal and genetic structure in a population of the European wild rabbit (Oryctolagus cuniculus). 773 26

Activin A, a member of the transforming growth factor beta supergene family, modulates DNA synthesis in cultured rat vascular smooth muscle cells (VSMC) (Kopma et al. (1993) Exp. Cell. Res. 206, 152-156). In the present study, we studied the production of activin A and follistatin in VSMC. When VSMCs cultured in a 24-well plate were cultured with 10% fetal calf serum (FCS) for 24 h, 0.94 +/- 0.20 pmol/well (mean +/- SE, n = 6) of bioactive activin was released into the culture media. Reverse-transcription polymerase chain-reaction revealed the expression of mRNA for the beta A subunit of inhibin but not for either the beta B or alpha subunit. Bioactivity of activin was increased in quiescent cells treated with FCS or platelet-derived growth factor (PDGF) but not with angiotensin II (Ang II) or insulin-like growth factor-I (IGF-I). Ang II or IGF-I did not stimulate DNA synthesis by itself but, when these two agents were combined, they increased nuclear labeling by 16.4% and release of bioactive activin by 170% of basal. The dose-response relationship and time course study indicated that PDGF-mediated release of activin correlated with initiation of DNA synthesis. Steady state expression of mRNA for the beta A subunit was markedly elevated 12 h after the addition of PDGF and was reduced thereafter. To assess the significance of autocrine activin, the effect of PDGF was determined in the presence and absence of excess of exogenous follistatin. The PDGF-mediated DNA synthesis was enhanced by the addition of excess follistatin.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1995 Feb 27
PMID:Production of activin A and follistatin in cultured rat vascular smooth muscle cells. 775 23

The acquisition of follicle-stimulating hormone (FSH) receptors during follicogenesis is believed to be a key event in the subsequent development of the follicle. We have examined the effect of FSH on FSH receptor mRNA in cultured rat granulosa cells by means of FSH receptor cRNA probe. Northern blot analysis indicated the existence of two predominant FSH receptor mRNA transcripts of approximately 5.5 and 2.4 kb in total RNA prepared from rat granulosa cells. Treatment of granulosa cell culture with FSH resulted in tentative suppression of FSH receptor mRNA level 2-6 h after treatment, with subsequent recovery at 24 h. Culture of granulosa cells for 6 h in the presence of increasing concentration of FSH resulted in a dose-dependent decrease in FSH receptor mRNA with a maximal suppression about 50% of control observed in response to 100 ng/ml FSH. We could not detect a similar effect on FSH receptor mRNA by 8-brom-adenosine 3,5-cyclic monophosphate (8-Br-cAMP; 0.2 mM) which showed continuous stimulation on FSH receptor mRNA during a similar time course. In this system, therefore, this transient down-regulation of FSH mRNA was not mediated by the cAMP pathway. Since the inhibitory effect of follistatin on activin-induced FSH binding to rat granulosa cells had been investigated, we studied the action of follistatin on the levels of activin-induced FSH receptor mRNA in rat granulosa cell culture.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1995 Feb 27
PMID:Regulation of follicle-stimulating hormone receptor messenger ribonucleic acid levels in cultured rat granulosa cells. 775 41

The aim of the present study was to investigate the sites and time of follistatin and inhibin alpha and beta A subunit gene expression during ovine follicular development and atresia. Prepubertal ovaries of 2-, 8- and 14-week-old ewe lambs (n = 9) were used. Regardless of age, the ovaries contained many follicles at different stages of development up to 2 mm in diameter, but large antral follicles were not found. Ovarian sections were hybridized with 35S-labelled antisense RNA probes transcribed from follistatin, inhibin alpha or inhibin beta A cDNA. Ovaries from mature gonadotrophin-stimulated ewes were used as controls. All three probes hybridized exclusively to granulosa cells, and not to other follicular or stromal cells. None of the probes hybridized to primordial follicles or primary follicles with less than two layers of granulosa cells. Follistatin mRNA was expressed strongly in the granulosa cells of all preantral follicles with two or more layers of cells, and in all non-atretic antral follicles. In addition, follistatin mRNA was found in some cells of the ovarian rete tubules. The inhibin alpha riboprobe hybridized to the granulosa cells of most preantral and all non-atretic antral follicles. In the preantral follicles, the strongest inhibin alpha expression was observed in the cells that were in close proximity to the oocyte. The inhibin beta A riboprobe hybridized exclusively to the granulosa cells of antral follicles. The labelling was observed either in the cumulus oophorus or in the cumulus oophorus and periantral granulosa cells of the non-atretic antral follicles. In adult ovaries, which were used as controls, the inhibin beta A riboprobe hybridized strongly to all granulosa cells of non-atretic large antral follicles. During follicular atresia, expression of all three mRNAs progressively decreased. In early atresia, inhibin beta A mRNA was observed only in the cells of the cumulus, whereas inhibin alpha and follistatin mRNAs were still present in the granulosa cells. As atresia progressed mRNA for inhibin alpha, and later also follistatin, disappeared. Our results suggest that there is a sequential appearance and disappearance of follistatin, inhibin alpha and inhibin beta A mRNAs during follicular development and atresia respectively. The marked expression of inhibin beta A in the cumulus cells implies a role of the oocyte in the differentiation of these cells.
J Mol Endocrinol 1994 Dec
PMID:Expression of mRNA for follistatin and inhibin/activin subunits during follicular growth and atresia. 789 43


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