Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interest in inhibin as a marker of ovarian malignancy was stimulated by the description of elevated immunoreactive inhibin levels in the sera of patients with granulosa cell tumours. Several groups have confirmed the value of serum inhibin in the diagnosis and follow-up of patients with this uncommon malignancy. Immunoreactive inhibin levels are also frequently elevated in patients with mucinous cystadenocarcinoma and less frequently in other forms of ovarian tumour. Assay of sera using the specific dimeric inhibin assays has shown that ovarian tumours are able to secrete dimeric inhibin particularly inhibin B. The less specific alpha-subunit directed assays, however, most frequently show elevated concentrations. Used in combination with CA125 as a dual tumour marker, it appears in principle that inhibin can be a useful diagnostic agent. Immunohistochemistry for the inhibin subunits has been reported with increasing frequency as a helpful method to assess suspected ovarian stromal cell tumours. Its diagnostic accuracy for other types of ovarian adenocarcinoma appears less reliable. Expression of the inhibin subunit mRNAs has been demonstrated in a variety of ovarian malignancies. The observation that inhibin levels are elevated in ovarian cancer has stimulated studies of their relevance to the molecular pathogenesis of these malignancies. Findings to date have been largely negative with no evidence for activating mutations of the FSH receptor or of the post-receptor signalling pathway proteins.
Mol Cell Endocrinol 2001 Jun 30
PMID:The inhibins and ovarian cancer. 1145 84

The aim of this study was to determine if follicle stimulating hormone receptor and luteinizing hormone receptor (FSH-R and LH-R) expression is altered on granulosa cells (GC) of women with low oestradiol responses to FSH. Cells were obtained from mature follicles (>17 mm) following controlled ovarian stimulation. For comparison, chinese hamster ovary (CHO) cells transfected with FSH-R or LH-R were also assessed. FSH-R and LH-R expression were detected by flow cytometry. Receptors were labelled with FSH-R antibodies, or with excess FSH or human chorionic gonadotrophin (HCG) and anti-FSH or HCG antibodies, and compared to multiple controls. Receptor expression on GCs was more heterogeneous than on CHO cells. Gonadotrophin receptor levels on GCs were not correlated with the number of FSH ampoules administered or peak oestradiol response. Low and normal response groups were defined using a ratio of peak oestradiol/number of FSH ampoules. FSH receptor expression was not different on GCs from low and normal responders. However, LH-R expression was higher on GCs of low responders compared to those of normal responders (P = 0.04 ) suggesting a trend to more advanced luteinization. Access of hormone to follicles was not reduced in low responders. Thus, differences in gonadotrophin receptor expression, hormone binding, and access of hormones to follicles do not appear to account for low oestradiol responses to FSH.
Mol Hum Reprod 2001 Aug
PMID:Gonadotrophin receptor expression on human granulosa cells of low and normal responders to FSH. 1147 Aug 56

Prenatal exposure of sheep to testosterone (T) disrupts ovarian cyclicity and leads to anovulation in adulthood. We propose that the disruption of ovarian function in prenatally-androgenized sheep is mediated via follicular defects stemming from reduced intrafollicular activin availability/action. The intra-follicular activin availability/action that facilitates follicular development is dictated by the relative proportions of activins, inhibins (antagonists of activin action) and follistatins (FS; binding proteins of activin and negator of activin action). Inhibin alpha, beta A, beta B, and FS mRNA expression were determined by in situ hybridization in 5 week-old ovaries from control (C) lambs or those exposed to testosterone (T) or DHT from 30-90 days of gestation. In utero exposure to T, but not DHT, increased total ovarian weight (0.4+/-0.1,1.5+/-0.5 and 0.3+/-0.1 g, C, T and DHT, respectively) and total number of follicles (16.5+/-2.8,37.8+/-7.9, and 18.8+/-3.0). With the exception of two follicles in T animals, all follicles were < or = 2 mm in diameter. All follicles < or = 2 mm in all groups expressed FSH receptor mRNA in the granulosa cells and LH receptor only in the thecal cells. The percentage of follicles expressing FS mRNA was increased (P<0.05) in sheep prenatally-androgenized with either T (80.4+/-8) or DHT (80.3+/-5.5) as compared to C (50.8+/-8.2). In contrast, the percentage of follicles expressing activin beta B mRNA tended to be lower (P=0.06) in the T (30.9+/-7.1) and DHT (40.5+/-3.3) groups as compared to C (66.1+/-15.6). Increased expression of FS along with the reduced expression of activin beta B mRNA provides evidence for compromised intra-follicular activin availability in the majority of follicles in the androgenized groups. The increase in ovarian weight and follicular number in the T, but not in the DHT group, suggests that the effects of T are mediated through the action of estrogen. We speculate that the decrease in relative abundance of activin may contribute to the selection defects in prenatally-androgenized sheep. If true, this may be a useful model to understand the etiology of polycystic ovarian syndrome.
Mol Cell Endocrinol 2001 Dec 20
PMID:Intra-follicular activin availability is altered in prenatally-androgenized lambs. 1173 94

Follicle stimulating hormone (FSH) is important for controlling spermatogenesis through binding with its receptor. However, little information is available on mutations of the FSH and its receptor gene in infertile men. To study the genetic defects, which caused problems in spermatogenesis, we screened the point mutations of the FSH receptor gene in infertile men with high serum FSH concentrations. Seventy male infertile patients with high FHS levels (> 12 mIU/ml) were screened for mutations in each of the 10 exons of the FSH receptor gene, using genomic DNA PCR and a single-strand conformation polymorphism (SSCP) analysis. From this study, three shifted bands were detected by SSCP. The first shifted band was found in the PCR product of exon 4, including the exon-intron boundary sequence in only one patient. The sequence analysis revealed a nucleotide A to T substitution in intron 3 (IVS3-4A-->T). The second shifted band was detected in exon 10 with high frequency (33%). A nucleotide A to G substitution was found at the position of the 994th nucleotide, predicting a Thr to Ala substitution at the position of the 307th amino acid (Thr307Ala). The third shifted band in the 3' region of exon 10 was detected frequently in infertile patient and normal groups. It was tightly linked to the Thr307Ala variant. Thus, all of the abnormalities represent neutral polymorphisms, and not pathological mutations of the FSH receptor gene. In conclusion, we did not confirm that the genomic mutation of the FSH receptor is a major genetic cause in Korean infertile patients with high FSH levels.
Mol Cells 2001 Dec 31
PMID:Mutation screening of the FSH receptor gene in infertile men. 1180 26

An Ala189Val mutation of the human FSH receptor (FSHR) has been found to cause hypergonadotrophic ovarian failure with arrest of follicular maturation in women, and suppressed spermatogenesis in men. We have now characterized the molecular mechanisms of the receptor inactivation. Wild-type and mutant FSHR cDNAs were expressed in monkey kidney (COS-7) cells and murine granulosa tumour (KK-1) cells. Similar steady-state levels of FSHR mRNA were found in COS-7 and KK-1 cells transfected with both types of FSHR cDNA. Conspicuously, immunofluorescence and confocal microscopy studies revealed that whereas the wild-type receptor could be readily detected on the plasma membrane, most of the mutated protein was intracellularly sequestered. Ligand binding studies confirmed the greatly reduced cell surface expression of the mutant FSHR. A low level of mutated receptors were expressed at the cell surface, as shown by ligand binding and cAMP response. The capacity of these receptors to evoke another second messenger response, that of inositol trisphosphate (IP3), was almost totally lost. This finding may be related to the clinical picture of the patients, i.e. blockade of follicular maturation. There is a highly conserved stretch of five amino acids (Ala-Phe-Asn-Gly-Thr) in the region of the mutation in all glycoprotein hormone receptors. We therefore created the same Ala to Val transition in the human LHR and studied its functional consequences. Similar functional alterations, i.e. intracellular sequestration and attenuated signal transduction, were found, as with mutated FSHR. Hence, this particular mutation in the conserved extracellular region of glycoprotein hormone receptors induces a conformational change that suppresses cell membrane targeting of the mutated receptor, probably through altered intracellular folding.
Mol Hum Reprod 2002 Apr
PMID:Functional characterization of the human FSH receptor with an inactivating Ala189Val mutation. 1191 78

Follicle-stimulating hormone (FSH) is an important regulator of follicular development. Some effects of FSH on ovarian follicles might be enhanced by androgens. The main objectives of the present study were to examine expression of the androgen receptor (AR) and FSH receptor (FSHR) in late developing follicles in pigs. Ovaries were collected from gilts on days 13, 15, 17, and 19 of the estrous cycle (day 0 = first day of estrus, n = 4 gilts/day), a period coincident with the follicular phase. One ovary was processed for immunohistochemistry (IHC) of AR. Samples of surface wall from the largest follicles (4-5 per gilt) were dissected from the other ovary, pooled and processed for determination of AR and FSHR mRNAs using reverse transcription-polymerase chain reaction (RT-PCR). Intense AR immunostaining was present in nuclei of granulosa cells of preantral and antral follicles. AR immunoreactivity was also present in the nuclei of oocytes. Weak staining for AR was observed in cells of the theca interna, ovarian surface epithelium, and in most cells of the ovarian stroma. Relative amounts of immunoreactive AR in granulosa cells of late developing follicles, or small antral follicles (< 2 mm), did not differ between days 13, 15, 17, and 19. However, amounts of AR in granulosa cells of small antral follicles was greater (P < 0.05) than in the largest follicles present in the same ovary. The relative amounts of AR mRNA in tissue from the largest follicles on days 13, 15, 17, and 19 did not differ; however, amounts of FSHR mRNA in the same follicles were not different between days 13, 15, and 17, but decreased (P < 0.05) by day 19. Results indicate that during the follicular phase in gilts, the AR protein is mainly present in granulosa cells. Relative amounts of AR protein in granulosa cells and mRNA in walls of late developing follicles did not significantly change from day 13 to 19; however, amounts of FSHR mRNA decreased in preovulatory follicles by day 19 of the estrous cycle.
Mol Reprod Dev 2002 May
PMID:Androgen receptor and follicle-stimulating hormone receptor in the pig ovary during the follicular phase of the estrous cycle. 1193 65

In mammals, gonadal functions are regulated by two pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), that interact with gonadal membrane receptors to activate adenylate cyclase. In comparison to mammalian systems, in squamate reptiles a reduced amount of information exists on gonadotropins and their related receptors. This study is aimed at clarifying if, in the lizard Podarcis sicula, the ovarian sensitivity to FSH is correlated to the reproductive cycle and to the expression of membrane receptors involved in the hormone recognition. The results demonstrate that the ovarian adenylate cyclase responsiveness to FSH parallels ovarian functions, being maximal during the ovulatory period. The ovarian sensitivity to FSH is also related to oocyte growth and vitellogenesis. Northern blot analyses reveal that the FSH receptor mRNA is maximally expressed in vitellogenic oocytes during the reproductive period. These results suggest that, in lizard ovary, hormone activation of adenylate cyclase is mediated by de novo synthesis of receptors specifically involved in FSH recognition. In lizards treated in vivo with FSH during the pre-ovulatory period, adenylate cyclase becomes refractory to further FSH stimulation 2 hr after treatment, but sensitivity to the hormone is restored after 2 weeks. Nevertheless, while the restored level of activity never exceeds that observed during the nonreproductive period, the expression level of FSH receptor mRNAs is significantly enhanced in these animals. These results suggest that in lizard the processes that regulate ovarian growth, vitellogenesis, and ovulation are controlled by a complex network of signals including gonadotropin, FSH receptor expression, and adenylate cyclase.
Mol Reprod Dev 2002 Jun
PMID:Relationship between adenylate cyclase sensitivity to follitropin and FSH receptor mRNA expression in the ovary of the lizard Podarcis sicula. 1198 31

Development, growth and function of the ovary are controlled by endocrine and paracrine signals. These may also influence the development of ovarian cancer. The aim of this study was to identify the key molecular markers of the unregulated growth and hormone synthesis seen in ovarian tumours, particularly in granulosa cell tumours (GCT). Genes used in this study were chosen on the basis of our understanding of growth and differentiation in the normal ovary. We sought to define the patterns of gene expression in a panel of epithelial and stromal ovarian tumours. Expression was determined by RT-PCR using gene-specific primers for the FSH receptor (FSHR); the FSH early response genes: regulatory subunit of protein kinase A (RII-beta), cyclin D2 (cycD2) and sgk; and late response markers: cyclooxygenase-2 (COX-2) and the LH receptor (LHR). The GCT had high expression of FSHR compared with normal ovaries and the other tumours. cycD2 and RII-beta and COX-2 genes were also highly expressed in the GCT. sgk and LHR expression was lower in all of the tumours than in normal ovaries. Serous cystadenocarcinomas also had an unexpectedly high expression of COX-2. Comparison of the gene expression profiles between each tumour group suggests a molecular phenotype for GCT that is similar to that reported for FSH stimulated pre-ovulatory granulosa cells.
Mol Hum Reprod 2002 May
PMID:FSH-regulated gene expression profiles in ovarian tumours and normal ovaries. 1199 39

Granulosa cell tumours (GCT) of the ovary arise from granulosa cells of the ovary on morphological, biochemical and molecular criteria. In order to understand the molecular pathogenesis of these tumours better we have sought to define their molecular phenotype, to identify activating mutations of the FSH-signalling pathway, to characterise their estrogen receptor expression and to explore the hypothesis that GCT may be resistant to inhibin. The pattern of gene expression observed in GCT suggests a phenotype which is similar to that of late preovulatory granulosa cells which would be consistent with activation of the FSH receptor signalling pathway, however, there is no evidence for activating mutations of either the FSH receptor or the associated trimeric G-proteins. Estrogen receptor beta is abundantly expressed in GCT. The various subunits and isoforms of the activin-inhibin receptor are expressed in GCT. These observations provide a basis for future studies of GCT, including further characterisation of signalling pathways known to be important in the regulation of granulosa cell growth and differentiation.
Mol Cell Endocrinol 2002 May 31
PMID:Molecular pathogenesis of granulosa cell tumours. 1204 22

Although a large number of naturally occurring activating mutations of the human LH receptor (hLHR) and human TSH receptor (hTSHR) have been identified, only one activating mutation of the human FSH receptor (hFSHR) has been found. Furthermore, mutations of several residues within the i3/transmembrane domain (TM) 6 region of the hFSHR that were done based upon known constitutively activating mutations of the human LHR were found to have no effect on hFSHR signaling. One of the hFSHR mutations examined in this context was the substitution of a highly conserved aspartate (D581) in TM6 with glycine. We show herein that although the basal activity of the rat FSHR (rFSHR) is similar to the hFSHR, mutation of the comparable residue (D580) in the rFSHR causes marked constitutive activation. Taking advantage of the high degree of amino acid identity between the rat and human FSHRs, we have used chimeras and point substitutions to determine the precise residues that suppress or permit constitutive activity by the D580/581G mutation. Thus, the simultaneous substitution of M576 in TM6 and H615 in TM7 of the hFSHR with the cognate rFSHR residues (threonine and tyrosine, respectively) now renders the hFSHR(D581G) mutant constitutively active. Conversely, the substitution of Y614 of the rFSHR with the cognate hFSHR residue (histidine) fully suppresses the constitutive activity of the rFSHR (D580G) mutant. Computer models of the human and rat FSHRs and mutants thereof were created based upon the crystal structure of rhodopsin. These models suggest that differences in hydrophobic interactions between TMs 6 and 7 of the rat and human FSHRs may account for the ability of TM6 of the rat, but not human, FSHR to adopt an active conformation as a result of the D580/581G mutation.
Mol Endocrinol 2002 Aug
PMID:Chimeras of the rat and human FSH receptors (FSHRs) identify residues that permit or suppress transmembrane 6 mutation-induced constitutive activation of the FSHR via rearrangements of hydrophobic interactions between helices 6 and 7. 1214 41


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