Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.27.1 (RNase)
 16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Follistatin, a glycosylated single chain protein that was originally isolated from ovarian follicular fluid, can specifically inhibit the biosynthesis and secretion of FSH by the pituitary. Follistatin has also been isolated from bovine pituitary and shown to have activin-binding activity. We wished to determine whether the follistatin gene is expressed in the rat pituitary and, if so, to identify the specific cell types. A 337-basepair fragment of the follistatin cDNA was amplified by polymerase chain reaction from a rat ovarian cDNA library and subcloned into pGEM3. Low levels of follistatin mRNA from rat pituitary poly(A)+RNA were detected by ribonuclease protection analysis using a specific follistatin riboprobe generated from the cDNA clone. The presence of follistatin mRNA in the pituitary was confirmed using polymerase chain reaction to amplify the follistatin cDNA generated by reverse transcription from total rat pituitary RNA. Furthermore, in situ hybridization studies combined with immunostaining for pituitary hormones were used to localize follistatin mRNA within the rat pituitary. When a biotinylated oligonucleotide complementary to follistatin mRNA was used with dispersed pituitary cells from rats in diestrus II, labeling was found in 5-7% of the cells. The in situ hybridization protocol was then combined with immunolabeling protocols for LH beta, FSH beta, or S-100 protein (a marker for folliculostellate cells). Follistatin mRNA was detected in 70 +/- 5% of LH beta cells, 44 +/- 11% of FSH beta cells, and 35 +/- 2% of folliculostellate cells. These results suggest that follistatin is expressed in pituitary gonadotropes and folliculostellate cells during diestrus II, where it may have a role in the local autocrine or paracrine regulation of FSH biosynthesis and secretion, possibly by binding to and modulating the effects of activin in the pituitary.
 ...
PMID:Follistatin gene expression in the pituitary: localization in gonadotropes and folliculostellate cells in diestrous rats. 157 12

Follistatin, a monomeric protein originally isolated from ovarian follicular fluid, is now believed to be a major local regulator of the multifaceted actions of activin by virtue of its activin-binding properties. In view of the ability of follistatin to stimulate progesterone production from granulosa cells and its presence in newly formed corpora lutea, the following study was conducted to determine the effects of cycle stage and pregnancy on follistatin gene expression and immunoreactivity in the rat ovary and uterus with the intent of gaining additional insights into the regulation of follistatin in these tissues. Decidua and placentas were also examined on days 15, 18, and 21 of pregnancy. Follistatin messenger RNA (mRNA) levels were quantified using a sensitive solution hybridization-RNase protection assay and values normalized to the amount of cyclophilin mRNA present in each sample. Levels of follistatin-like immunoreactivity (FLI) in serum and tissues were estimated using a homologous porcine follistatin RIA. Follistatin message levels in the ovary increased between proestrus and estrus with a return to proestrous values on both days of diestrus. In the nonpregnant uterus, mRNA levels on proestrus were similar to levels measured in uteri taken from hypophysectomized or ovariectomized rats. Interestingly, follistatin gene expression increased almost 3-fold between proestrus and estrus. An additional experiment demonstrated that this increase could be abated by treatment of proestrous rats with pentobarbital which blocks preovulatory rises in serum progesterone levels and could be restored by administration of progesterone to pentobarbital-treated proestrous rats. In pregnant rats, ovarian follistatin message levels on days 3 and 6 of pregnancy were identical to levels observed on day 2 of diestrus. However, an abrupt 4-fold increase in ovarian mRNA levels occurred between days 6 and 9 with a further 58% increase occurring by day 12. This marked increase in message levels was unaccompanied by changes in ovarian FLI levels. A precipitous decrease in transcript levels accompanied by a decline in FLI levels then followed with ovarian gene expression on days 15 through 21 being slightly higher than expression during the initial stages of gestation. Expression of the gene in the decidua and placenta did not vary between days 15 and 21 of pregnancy. Levels of FLI in serum also were invariant during the cycle and pregnancy.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Effects of estrous cycle stage and pregnancy on follistatin gene expression and immunoreactivity in rat reproductive tissues: progesterone is implicated in regulating uterine gene expression. 846 76

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.
 ...
PMID:Structural and functional characterization of the rat follistatin (activin-binding protein) gene promoter. 847 73

Activins and follistatins regulate all levels of the reproductive axis, including the pituitary where they stimulate and inhibit FSH production, respectively. Gonadotropes are known to express inhibin/activin betaB and activin-B (betaBbetaB) functions as an autocrine modulator of FSH production. By contrast, the mRNA for the activin-binding protein, follistatin, is present in most pituitary cells and folliculo-stellate cells may be the major source of the protein secreted by the anterior pituitary. Interleukin-1beta (IL-1beta) is one of several cytokines known to also influence the reproductive axis. IL-1beta inhibits the hypothalamo-pituitary-gonadal (HPG) axis by suppressing GnRH and gonadal steroid production. Because several pituitary cell types, including follistatin-producing folliculo-stellate cells, are targets of IL-1beta, cytokine effects on gonadotrope function were evaluated using cultured rat anterior pituitary cells. Activin-A (0.01 to 1 nM; 24h) increased basal FSH secretion approximately 2-fold. IL-1beta (0.005 to 0.5 nM) by itself had no effect on basal FSH secretion. However, IL-1beta attenuated FSH secretion in response to all concentrations of activin-A. These results suggest that the cytokine might stimulate the local production of a factor, such as follistatin, that antagonizes the action of activin-A. RNase protection analysis indicated that IL-1beta (0.005 to 5 nM) stimulated follistatin and inhibin/activin betaB mRNA accumulation in a time-dependent manner. These in vitro effects of IL-1beta were blocked by the specific IL-1 receptor antagonist (IL-lra) and were not mimicked by either rhIL-6 or lipopolysaccharide (LPS). Treatment of intact male rats with LPS (50 microg, i.v.), which increases plasma IL-1beta and induces IL-1beta expression in many tissues, including the pituitary, produced similar time-dependent increases in pituitary follistatin and inhibin/activin subunit mRNA levels. These results suggest that IL-1beta can modulate gonadotrope responses to activins by influencing the local balance of activin-B and follistatin within the pituitary.
 ...
PMID:Interleukin-1beta regulates pituitary follistatin and inhibin/activin betaB mRNA levels and attenuates FSH secretion in response to activin-A. 964 13

Follistatin is a secreted protein, which functions as an antagonist of different members of the TGF-beta superfamily, including activin and bone morphogenetic proteins. Expression of follistatin is tightly regulated during mouse development both spatially and temporally. In order to study the regulation of follistatin expression in the mouse embryo we have cloned and analyzed part of the 5' flanking region of the murine follistatin gene. Primer extension and RNase protection assays demonstrate that the murine follistatin promoter region has at least three distinct transcription initiation sites, which are each preceded by a TATA box. All of the transcription initiation sites are located within the first 500 bp upstream of the translational start site. Sequence analysis of this 500 bp region revealed several consensus binding sites for transcription factors including AP-1, Brachyury-T, CREB, Sp1, AP-2 and Tcf. To test whether the 5' region displays promoter activity, we transfected various 5' flanking region deletion constructs into F9 embryonal carcinoma (EC) cells and into P19 EC cells. In these two cell lines a region of only 262 bp upstream of the translation start site could drivereporter expression in a manner that reflects endogenous mRNA expression.
 ...
PMID:Cloning and analysis of the mouse follistatin promoter. 1125 2

In rats, FSHbeta gene expression and FSH secretion are increased and decreased, respectively, by pituitary activin and follistatin. Because little information is available on the paracrine control of FSH secretion in the primate, follistatin and activin/inhibin beta(B) messenger RNA (mRNA) levels were measured in pituitaries of adult male rhesus monkeys 6 weeks after castration or sham surgery (n = 5/group). Follistatin mRNA was determined by quantitative RT-PCR assay using oligonucleotide primers designed to span exons 3-5 of the human follistatin gene. Activin/inhibin beta(B) mRNA levels were measured by ribonuclease protection. Orchidectomy resulted in a 100-fold increase in plasma FSH concentrations and a 60-fold rise in those of LH. In castrated monkeys, levels of mRNA encoding FSHbeta, LHbeta, alpha- subunit, and GnRH receptor (GnRH-R) were increased 21-, 2.1-, 1.7-, and 1.7-fold, respectively (P < 0.01). Levels of pituitary follistatin and activin/inhibin beta(B) mRNAs, however, were similar in castrated and intact animals. These data suggest that the paracrine control of FSH secretion in the male differs substantially in primates and rodents. Specifically, the relatively greater postcastration rise in FSHbeta gene expression and FSH secretion in the adult male monkey may result because in this species pituitary follistatin gene expression does not increase after orchidectomy, as it does in the rat.
 ...
PMID:Pituitary follistatin and activin gene expression, and the testicular regulation of FSH in the adult Rhesus monkey (Macaca mulatta). 1141 6

The activin-follistatin system is a potent growth regulatory system of liver tissue homeostasis. Activin A inhibits hepatocellular DNA synthesis and induces cell death. Follistatin binds activin and sequesters it from the signaling pathway. Consistently, follistatin has been reported to act as an inducer of DNA synthesis in the liver. Using RNase protection analysis, we studied the expression of follistatin in rat and mouse liver tumors as a possible mechanism to overcome activin growth control. Approximately 40% of the tumors (nine of 24 each), most of them hepatocellular carcinomas, displayed increased levels of follistatin mRNA when compared to tumor-surrounding liver tissue. The degree of overexpression was highly variable but independent of the carcinogen treatment that animals had received. It was also independent from the histological stage of malignancy and further found in rat liver adenomas. Follistatin expression was also observed in cell lines derived from human hepatocellular carcinomas. Overexpression of follistatin may represent a unique strategy of hepatic tumors to overcome the inhibitory action of a growth factor, activin, by decreasing its local bioavailability.
 ...
PMID:Follistatin overexpression in rodent liver tumors: a possible mechanism to overcome activin growth control. 1220 61