Stanniocalcin (STC) is a calcium-regulated hormone in bony fishes. The hormone was so named because it is
synthesized by the corpuscles of Stannius, endocrine glands that are associated with the kidneys of all fishes with a bony
skeleton. The primary function of STC in fishes is the prevention of hypercalcemia. Olsen et al. (1996) isolated a human cDNA clone encoding the mammalian homolog of STC.
Human STC was found to be 247 amino acids long and to share 73% amino acid sequence similarity with fish STC.
NCBI Summary:
This gene encodes a secreted, homodimeric glycoprotein that is expressed in a wide variety of tissues and may have autocrine or paracrine functions. The gene contains a 5' UTR rich in CAG trinucleotide repeats. The encoded protein contains 11 conserved cysteine residues and is phosphorylated by protein kinase C exclusively on its serine residues. The protein may play a role in the regulation of renal and intestinal calcium and phosphate transport, cell metabolism, or cellular calcium/phosphate homeostasis. Overexpression of human stanniocalcin 1 in mice produces high serum phosphate levels, dwarfism, and increased metabolic rate. This gene has altered expression in hepatocellular, ovarian, and breast cancers. [provided by RefSeq, Jul 2008]
General function
Ligand, Hormone
Comment
Paracrine Regulation of Ovarian Granulosa Cell Differentiation by Stanniocalcin 1 (STC1): Mediation Through Specific STC1 Receptors
Luo CW,et al .
Stanniocalcin (STC) in fish maintains calcium and phosphate homeostasis whereas mammalian STC1 shows a diverse tissue expression pattern with ovary exhibiting the highest level. Based on the known expression of STC1 in theca/interstitial cells of the ovary, we generated recombinant N-glycosylated STC1 proteins and tested its ability to modulate granulosa cell differentiation. In cultured rat granulosa cells obtained from early antral follicles, treatment with STC1 suppressed FSH-stimulated progesterone biosynthesis with minimal effects on estradiol and cAMP production. In mature granulosa cells, treatment with STC1 also suppressed hCG-induced progesterone production. The inhibitory effect of STC1 was accompanied by a pronounced suppression of the CYP11A transcripts and the FSH induction of functional LH receptors. In addition, STC1 was found to act downstream of adenyl cyclases in suppressing progesterone biosynthesis. We also tested the regulation of STC1 gene expression by gonadotropins. Treatment with pregnant mare serum gonadotropin decreased STC1 transcript levels in theca cells of maturing follicles whereas subsequent treatment with hCG led to sustained suppression in the corpora lutea. Using radiolabeled recombinant STC1, receptor assays showed specific STC1 binding with a high affinity to granulosa cells. Because STC1 is expressed in ovarian theca/interstitial cells, the present demonstration of receptor binding and the specific actions of STC1 in granulosa cells suggest the existence of a follicular paracrine system in which theca cell-derived STC1 dampens the gonadotropin stimulation of granulosa cell differentiation. The observed STC1 suppression of progesterone, but not estradiol, production further suggests the potential role of this paracrine hormone as a luteinization inhibitor.
Cellular localization
Secreted
Comment
Ovarian function
Steroid metabolism, Luteolysis, Oocyte maturation
Comment
STC1 affects redox status of swine granulosa cells. Baioni L et al. Stanniocalcin 1 (STC1) is a glycoprotein hormone expressed in different mammalian tissues. In previous studies, we showed STC1 expression in swine ovarian follicles and we demonstrated that STC1 may be a physiological regulator of follicular function. Since reactive oxygen species (ROS) are important signal transducers in the ovary, the present study was undertaken to investigate STC1 action on ROS generation and on the activity of the major enzymatic and non-enzymatic scavengers in swine granulosa cells. O(2)- generation, catalase activity and FRAP levels were increased by STC1, whereas H(2)O(2) generation and peroxidase activity were decreased by STC1. Taken together, our data show that STC1 modulates redox status in swine granulosa cells.Chang et al. (1995) isolated human STC cDNAs. Using Northern blot analysis, they found that STC is
expressed as a 4-kb mRNA and a less abundant 2-kb mRNA in several human tissues, with the strongest expression in
ovary, prostate, and thyroid.
Regulation by vitamin D(3) of expression of the genes for stanniocalcins 1 and 2 (STC-1 and STC-2)
was studied by Honda S et al and their levels were shown to be oppositely
regulated in the kidney and to remain
unaffected in the ovary. Female rats were treated with
calcitriol, the active form of vitamin D(3), and
alterations in the levels of STC-1 and STC-2 mRNA were
determined by Northern blot analysis in the
ovary where the STC-1-expressing cells have
previously been identified by in situ
hybridization histochemistry. In the ovary, both STC-1
and STC-2 mRNA levels were not significantly affected by
the calcitriol treatment.
Worthington RA et al test the specificity of the antibody against recombinant stanniocalcin and found this protein in rat bladder, ovary and
kidney.
Paciga M, et al 2003 reported the targeting of stanniocalcin ligand and receptor to lipid storage droplets of steroidogenic cells.
Stanniocalcin (STC) is a large polypeptide hormone that is widely distributed in tissues such as kidney, adrenal and ovary. In most tissues, STC exists as a 50 kDa homodimer (STC(50)). The ovaries produce a higher molecular weight variant (big STC) in androgen-producing theca cell and interstitial cell compartments. Luteal cells, which do not express the STC gene, nonetheless contain high levels of STC protein, suggesting they are targeted by and sequester big STC through a receptor-mediated process. Recently, a STC-alkaline phosphatase fusion protein (STC-AP) was used to characterize mitochondrial targeting and sequestration of STC(50) and its receptor in liver and kidney. The main objective of the present study was to characterize big STC and its receptor in mammalian ovary and to determine if the ovarian STC variant was similarly targeted to luteal cell mitochondria. By in situ ligand binding, we identified large numbers of STC receptors on corpus luteal cells. However, a more detailed analysis of sub-cellular fractions revealed that both STC and its receptor were not preferentially targeted to mitochondria, but instead to cholesterol / lipid storage droplets, which was more indicative of a role in steroidogenesis. Functional studies revealed that additions of big STC had concentration-dependent inhibitory effects on both basal and stimulated progesterone output by primary cultured luteal cells. Furthermore, STC receptor levels were up-regulated in luteal cells in response to protein kinase A activation. Taken together, these findings indicate that theca cell-derived big STC is targeted to the cholesterol / lipid storage droplets of steroidogenic cells to regulate steroidogenesis. This constitutes the first reported description of polypeptide hormone and receptor targeting to cholesterol / lipid droplets and the first biological role for the big STC variant.
Evidence for cross-talk between stanniocalcins
Paciga M, et al .
There are 2 forms of stanniocalcin (STC) produced by the STC-1 gene; a 50 kDa polypeptide known as STC50 and a recently discovered group of higher molecular weight variants that are collectively referred to as big STC. Both have different tissue patterns of expression and different intracellular targeting pathways. STC50 functions locally in tissues such as muscle, liver, and kidney and is targeted to mitochondria. Big STC, on the other hand, is made by the ovaries. It signals both locally on nearby corpus luteal cells and systemically. Interestingly, however, receptor binding assays employing STC50 as the tracer have shown that the smaller ligand can bind equally to tissue receptors targeted by either form of the hormone. This suggests there may be cross-talk between ligands. The present study provides credence to this notion by demonstrating how the 2 hormones can compete for tissue receptors normally targeted by 1 form of the hormone (big STC). The results also reveal how STC50 can completely block the inhibitory effects of big STC on luteal cell progesterone release when added simultaneously. The findings therefore add credence to the possibility that there may be circumstances during which the 2 ligands functionally antagonize each other's actions.
/////////The proteolytic activity of pregnancy-associated plasma protein-A is potentially regulated by stanniocalcin-1 and -2 during human ovarian follicle development. Jepsen MR et al. (2016) Is the proteolytic activity of pregnancy-associated plasma protein-A (PAPP-A) regulated by the stanniocalcins (STC1 and STC2) during human follicle maturation? The STCs and PAPP-A show similar expression by immunohistochemistry in developing follicles, and regulation of PAPP-A proteolytic activity is suggested by the identification of inhibited protein complexes between PAPP-A and STC1 or STC2 in human follicular fluid (FF). The insulin-like growth factor (IGF)-regulating proteinase PAPP-A is secreted by the granulosa cells of estrogen-dominant follicles and is involved in follicle growth. STC1 and STC2 have recently been identified as novel PAPP-A inhibitors, and their expression in non-human mammalian ovaries has previously been observed. The proteolytic activity of PAPP-A in human follicular fluid was assessed, and the interaction between PAPP-A and the STCs in human ovarian tissues and follicular fluid was analyzed using immunoassays. From 21 women, matched pairs of follicular fluid were obtained from one follicle just prior to final maturation of follicles with human chorionic gonadotrophin (hCG), and from another follicle in connection with oocyte aspiration after hCG treatment. Ovarian tissues were obtained from women having one ovary removed for fertility preservation by cryopreservation prior to gonadotoxic treatment. The concentration and activity of PAPP-A were determined in all samples of follicular fluid. Furthermore, to investigate PAPP-A regulation during follicle development, immunohistochemical staining of PAPP-A, STC1, and STC2 was performed on pre-antral and antral human follicles. To attempt the demonstration of native complexes between PAPP-A and the STCs, immunoprecipitation from a pool of human follicular fluid was performed. The concentration of PAPP-A antigen in follicular fluid increased upon stimulation of ovulation with hCG (P < 0.02), but at the same time, PAPP-A activity was decreased. PAPP-A, STC1, and STC2 were localized together in primordial, late primary, and antral follicles, indicating that complex formation is possible in ovarian tissue. Covalent PAPP-A:STC2 and non-covalent PAPP-A:STC1 complexes were immunoprecipitated from follicular fluid, documenting for the first time native inhibited complexes between PAPP-A and the STCs. We have demonstrated the presence of native complexes between PAPP-A and the STCs in the human ovary, indicating STC-mediated PAPP-A proteolytic inhibition. Further investigation is required to extend this principle to other tissues. Our data suggest that the STCs contribute to PAPP-A regulation during folliculogenesis and support a general model in which STC1 and STC2 are regulators of mammalian IGF activity through inhibition of PAPP-A. We suggest that future functional studies take both PAPP-A and the STCs into consideration. This work was supported by grants from the Novo Nordisk Foundation, and the Danish Council for Independent Research. No competing interests declared.//////////////////
Expression regulated by
LH, Steroids
Comment
Effects of miR-101-3p on goat granulosa cells in vitro and ovarian development in vivo via STC1. An X et al. (2020) MiRNAs act as pivotal post-transcriptional gene mediators in the regulation of diverse biological processes, including proliferation, development and apoptosis. Our previous study has showed that miR-101-3p is differentially expressed in dairy goat ovaries compared single with multiple litters. The objective of this research was to explore the potential function and molecular mechanism of miR-101-3p via its target STC1 in goat ovarian growth and development. cDNA libraries were constructed using goat granulosa cells transfected with miR-101-3p mimics and negative control by RNA-sequencing. In total, 142 differentially expressed unigenes (DEGs) were detected between two libraries, including 78 down-regulated and 64 up-regulated genes. GO and KEGG enrichment analysis showed the potential impacts of DEGs on ovarian development. STC1 was singled out from DEGs for further research owing to it regulates reproductive-related processes. In vitro, bioinformatics analysis and 3'-UTR assays confirmed that STC1 was a target of miR-101-3p. ELISA was performed to detect the estrogen (E2) and progesterone (P4) levels. CCK8, EdU and flow cytometry assays were performed to detect the proliferation and apoptosis of granulosa cells. Results showed that miR-101-3p regulated STAR, CYP19A1, CYP11A1 and 3β-HSD steroid hormone synthesis-associated genes by STC1 depletion, thus promoted E2 and P4 secretions. MiR-101-3p also affected the key protein PI3K, PTEN, AKT and mTOR in PI3K-AKT pathway by STC1, thereby suppressing proliferation and promoting apoptosis of granulosa cells. In vivo, the distribution and expression levels of miR-101-3p in mouse ovaries were determined through fluorescence in situ hybridisation (FISH). Immunohistochemistry results showed that STC1 expression was suppressed in mouse ovaries in miR-101-3p-agonist and siRNA-STC1 groups. Small and stunted ovarian fragments, decreased numbers of follicles at diverse stages were observed using Hematoxylin-eosin (HE) staining, thereby showing unusual ovarian development after miR-101-3p overexpression or STC1 depletion. Inhibition of miR-101-3p manifested opposite results. Taken together, our results demonstrated a regulatory mechanism of miR-101-3p via STC1 in goat granulosa cells, and offered the first in vivo example of miR-101-3p and STC1 functions required for ovarian development.//////////////////
Paciga M, et al reported that ovarian stanniocalcin is structurally unique in mammals and its
production and release are regulated through the luteinizing
hormone receptor.
They found that forskolin significantly
increased STC gene expression and secretion by both rat and bovine TICs, an
effect that was only replicated by human (h) chorionic gonadotropin (CG).
Coincubation of TICs with hCG and phosphodiesterase inhibitors further
increased STC secretion, whereas coincubation of TICs with hCG and protein
kinase A inhibitors attenuated hCG-stimulated release. Intriguingly, ovarian
STC proved to be substantially larger than the 50-kDa homodimer produced in
most other tissues. These results indicate that ovarian STC is physically
distinct, a feature that could explain its presence in serum during pregnancy
and lactation.
Paciga M, et al reported the regulation of luteal cell big stanniocalcin production and secretion.
In mammals, the ovaries have the highest levels of stanniocalcin (STC) gene expression, most or all of which is confined to androgen-producing thecal-interstitial cells (TICs). Ovarian TICs also synthesize a different STC that consists of three high molecular weight species collectively known as big STC. Upon release in response to LH stimulation, TIC-derived big STC is sequestered locally by target cells, particularly steroidogenic cells of the corpus luteum, via a receptor-mediated process. Although there is little or no STC gene expression in luteal cells in the in vivo setting, this report describes how the gene is turned on, STC mRNA becomes readily detectable, and big STC is secreted when bovine luteal cells are cultured in vitro. STC gene expression and secretion were both positively regulated by activation of the adenylate cyclase/protein kinase A signaling pathway (forskolin and 8-bromo-cAMP). However, prostaglandin E2 was the only natural luteal cell ligand capable of replicating the effects of forskolin and 8-bromo-cAMP (LH had no consistent effect). Sex steroids such as 17beta-estradiol, androstenedione, and progesterone significantly decreased luteal cell STC expression and secretion. However, only androstenedione was capable of reducing STC production and secretion to undetectable levels. This report is the first to show that once removed from their normal context within the ovary, luteal cells are capable of synthesizing and secreting big STC. It is also the first to delineate the regulatory mechanisms involved in STC production and secretion by luteal cells. These results therefore suggest that under certain physiological conditions, the corpus luteum could very well serve as a source of STC production.
New candidate genes to predict pregnancy outcome in single embryo transfer cycles when using cumulus cell gene expression. Wathlet S et al. OBJECTIVE: To relate the gene expression in cumulus cells surrounding an oocyte to the potential of the oocyte, as evaluated by the embryo morphology (days 3 and 5) and pregnancy obtained in single-embryo transfer cycles. DESIGN: Retrospective analysis of individual human cumulus complexes using quantitative real-time polymerase chain reaction for 11 genes. SETTING: University hospital IVF center. PATIENT(S): Thirty-three intracytoplasmic sperm injection patients, of which 16 were pregnant (4 biochemical and 12 live birth). INTERVENTION(S): Gene expression analysis in human cumulus complexes collected individually at pickup, allowing a correlation with the outcome of the corresponding oocyte. Multiparametric models were built for embryo morphology parameters and pregnancy prediction to find the most predictive genes. MAIN OUTCOME MEASURE(S): Gene expression profile of 99 cumulus complexes for 11 genes. RESULT(S): For embryo morphology prediction, TRPM7, ITPKA, STC2, CYP11A1, and HSD3B1 were often retained as informative. Models for pregnancy-biochemical or live birth-complemented or not with patient and cycle characteristics, always retained EFNB2 and CAMK1D together with STC1 or STC2. Positive and negative predictive values of the live birth models were >85%. CONCLUSION(S): EFNB2 and CAMK1D are promising genes that could help to choose the embryo to transfer with the highest chance of a pregnancy.
In situ
hybridization revealed strong, specific hybridization of STC over the thecal-interstitial cells of the ovarian stroma,
whereas immunohistochemical analysis indicated
that STC was present not only in the stroma, but also in
the corpora lutea and oocyte of the developing
follicle Varghese R et al . Consequently, STC may act as a signaling
molecule between the thecal-interstitial cell
compartment and the corpus luteum and oocyte, thereby
regulating the activity of these structures in
some way.
Christopher R. McCudden et al 2001 reported that ovarian Stanniocalcin in Trout Is Differentially Glycosylated and
Preferentially Expressed in Early Stage Oocytes.
The STC gene expression was
highest in early stage oocytes and diminished progressively as oocytes developed. At the cellular level, ovarian STC gene expression was most
abundant in the ooplasm of early stage oocytes, but it was also weakly evident
in the theca
layer, interstitial cells, and vitellogenic oocytes.
Expression and localization of stanniocalcin 1 in swine ovary. Basini G et al. Stanniocalcin 1 (STC 1) is a glycoprotein involved in mineral homeostasis and was first identified in fish. Its mammalian homologue has been implicated in the regulation of various biological processes, including angiogenesis and steroidogenesis both of which are fundamental events in ovarian function. Interestingly, the highest level of STC 1 expression in mammals occurs in ovarian tissue but no information is available on swine species. Therefore, the present study was undertaken to investigate the expression and the immunolocalization of STC 1 in swine ovary. In addition, we evaluated whether swine granulosa cells synthesize STC 1 and its possible modulation by hypoxia, a physiological condition in ovarian follicle growth. Our data show STC 1 for the first time in swine ovary; moreover, we demonstrate STC 1 production by granulosa cells, both in basal condition and in response to oxygen deprivation. The latter is suggestive of a potential modulatory role for STC 1 in hypoxia-driven angiogenesis.
Izhar
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Deol HK, et al 2000 reported that during postnatal development the pattern of
stanniocalcin (STC) gene expression begins to become thecal-restricted as early
as day 5 and achieves the adult pattern of expression by two weeks of age. During
postnatal development the primary sites of STC protein localization are the theca
and oocytes and after maturation it is also strongly concentrated in the corpora
lutea. In the superovulation model,
however, we observed a significant increase in STC messenger RNA (mRNA)
levels after treatment with hCG implying regulation by LH. During gestation the
expression of ovarian STC increases 15-fold and is localized to the
theca-interstitial cells with lower expression also being found in the corpora
lutea. STC also becomes detectable in the serum for the first time suggesting an
endocrine role for STC during gestation. Also striking is the intense STCir staining found
in oocytes as they are devoid of STC mRNA, thus implying a role for STC in
oocyte maturation. REGULATION OF LUTEAL CELL BIG STANNIOCALCIN PRODUCTION AND SECRETION.
Paciga M,et al 2004 .
In mammals, the ovaries have the highest levels of stanniocalcin (STC) gene expression, most or all of which is confined to androgen-producing theca-interstitial cells (TICs). Ovarian TICs also synthesize a different STC that consists of three high molecular weight species collectively known as big STC. Upon release in response to LH stimulation, TIC-derived big STC is sequestered locally by target cells, particularly steroidogenic cells of the corpus luteum, via a receptor-mediated process. Although there is little or no STC gene expression in luteal cells in the in vivo setting, this report describes how the gene is turned on, STC mRNA becomes readily detectable and big STC is secreted when bovine luteal cells are cultured in vitro. STC gene expression and secretion were both positively regulated by activation of the adenylate cyclase / protein kinase A signaling pathway (forskolin and 8Br-cAMP). However, prostaglandin E2 was the only natural luteal cell ligand capable of replicating the forskolin and 8Br-cAMP effects (LH had no consistent effects). Sex steroids such as estradiol-17beta, androstenedione and progesterone significantly decreased luteal cell STC expression and secretion. However, only androstenedione was capable of reducing STC production and secretion to undetectable levels. This report is the first to show that once removed from their normal context within the ovary, luteal cells are capable of synthesizing and secreting big STC. It is also the first to delineate the regulatory mechanisms involved in STC production and secretion by luteal cells. These results therefore suggest that under certain physiological conditions, the corpus luteum could very well serve as a source of STC production.
Paciga M,et al 2004 reported the REGULATION OF LUTEAL CELL BIG STANNIOCALCIN PRODUCTION AND SECRETION.
In mammals, the ovaries have the highest levels of stanniocalcin (STC) gene expression, most or all of which is confined to androgen-producing theca-interstitial cells (TICs). Ovarian TICs also synthesize a different STC that consists of three high molecular weight species collectively known as big STC. Upon release in response to LH stimulation, TIC-derived big STC is sequestered locally by target cells, particularly steroidogenic cells of the corpus luteum, via a receptor-mediated process. Although there is little or no STC gene expression in luteal cells in the in vivo setting, this report describes how the gene is turned on, STC mRNA becomes readily detectable and big STC is secreted when bovine luteal cells are cultured in vitro. STC gene expression and secretion were both positively regulated by activation of the adenylate cyclase / protein kinase A signaling pathway (forskolin and 8Br-cAMP). However, prostaglandin E2 was the only natural luteal cell ligand capable of replicating the forskolin and 8Br-cAMP effects (LH had no consistent effects). Sex steroids such as estradiol-17beta, androstenedione and progesterone significantly decreased luteal cell STC expression and secretion. However, only androstenedione was capable of reducing STC production and secretion to undetectable levels. This report is the first to show that once removed from their normal context within the ovary, luteal cells are capable of synthesizing and secreting big STC. It is also the first to delineate the regulatory mechanisms involved in STC production and secretion by luteal cells. These results therefore suggest that under certain physiological conditions, the corpus luteum could very well serve as a source of STC production.
Phenotypes
Mutations
1 mutations
Species: None
Mutation name: None
type: None fertility: None Comment: The Murine Stanniocalcin 1 Gene Is Not Essential for Growth and Development Chang AC, et al .
The stanniocalcin 1 (STC1) gene is expressed in a wide variety of tissues, including the kidney, prostate, thyroid, bone, and ovary. STC1 protein is considered to have roles in many physiological processes, including bone development, reproduction, wound healing, angiogenesis, and modulation of inflammatory response. In fish, STC1 is a hormone that is secreted by the corpuscles of Stannius and is involved in calcium and phosphate homeostasis. To determine the role of STC1 in mammals, we generated Stc1-null mice by gene targeting. The number of Stc1(-)(/)(-) mice obtained was in accordance with Mendelian ratios, and both males and females produced offspring normally. No anatomical or histological abnormalities were detected in any tissues. Our results demonstrated that Stc1 function is not essential for growth or reproduction in the mouse.