The Smad signalling pathway is critical for transmitting transforming growth
factor-beta (TGF-beta) superfamily signals from the cell surface to the nucleus. In
the nucleus, Smads regulate transcriptional responses by recruiting co-activators and
co-repressors to a wide array of DNA-binding partners. Thus, Smads function as
transcriptional co-modulators to regulate TGFbeta-dependent gene expression.
NCBI Summary:
The protein encoded by this gene is involved in the transforming growth factor beta signaling pathway that results in an inhibition of the proliferation of hematopoietic progenitor cells. The encoded protein is activated by bone morphogenetic proteins type 1 receptor kinase, and may be involved in cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
General function
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Germ cell development
Comment
SMAD1/5 mediates bone morphogenetic protein 2-induced up-regulation of BAMBI expression in human granulosa-lutein cells. Bai L et al. (2017) Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is a transforming growth factor β (TGF-β) type I receptor antagonist that negatively regulates TGF-β and bone morphogenetic protein (BMP) signaling. BAMBI has been shown to be regulated by TGF-β signaling; however, whether BAMBI can be regulated by BMP signaling remains to be determined. The aim of this study was to investigate the effect of BMP2 on the regulation of BAMBI expression in human granulosa-lutein cells and the underlying mechanisms. Both primary and immortalized human granulosa-lutein cells were used as research models. Using dual inhibition approaches, our results showed that BMP2 activated SMAD1/5/8 phosphorylation and up-regulated BAMBI mRNA levels, which was reversed by the BMP type I receptor inhibitors, DMH-1 and dorsomorphin, but not by SB431542 (activin/TGF-β type I receptor inhibitor). Moreover, the combined knockdown of SMAD1 and SMAD5 completely abolished the BMP2-induced up-regulation of BAMBI. Similarly, knockdown of SMAD4 reversed the BMP2-induced up-regulation of BAMBI. Pre-treatment with BMP2 inhibited the TGF-β1-induced phosphorylation of SMAD2/3 and up-regulation of MMP2, and these inhibitory effects were reversed by knockdown of endogenous BAMBI. Our findings indicate that BAMBI is a BMP-responsive gene and that BAMBI participates in the negative feedback regulation of TGF-β signaling in the human ovary.//////////////////
Chang H, et al 2001 reported that Smad5 is required for mouse primordial germ cell development.
Smad5, together with Smad1 and Smad8, have been implicated as downstream
signal mediators for several bone morphogenetic proteins (BMPs). Recent studies
have shown that primordial germ cells (PGCs) are absent or greatly reduced in
Bmp4 or Bmp8b mutant mice. To define the role of Smad5 in PGC development,
the authors examined PGC number in Smad5 mutant mice by Oct4 whole-mount in situ
hybridization and alkaline phosphatase staining and found ectopic PGC-like cells
in the amnion of some Smad5 mutant mice, however, the total number of PGCs
was greatly reduced or completely absent in Smad5 mutant embryos, similar to
Bmp4 or Bmp8b mutant embryos. Therefore, Smad5 is an important factor
involved in PGC generation and localization.
Expression regulated by
Growth Factors/ cytokines, AMH, mir27a
Comment
Functional characterization of microRNA-27a-3p expression in human polycystic ovary syndrome. Wang M et al. (2017) The goal of this study was to characterize the function of microRNA-27a-3p (miR-27a-3p) in polycystic ovary syndrome (PCOS). MiR-27a-3p expression was analyzed in excised granulosa cells (GCs) from 21 PCOS and 12 normal patients undergoing IVF cycle treatments, and in 17 non-treated cuneiform ovarian resection PCOS samples and 13 control ovarian samples-from non-PCOS patients. We found that the expression of miR-27a-3p was significantly increased in both excised GCs and the ovaries of PCOS patients compared to the controls. Insulin treatment of the human granulosa-like tumor cell line KGN resulted in decreased downregulated the expression of miR-27a-3p, and this effect appeared to be mediated by STAT1 and STAT3. The overexpression of miR-27a-3p in KGN cells inhibited SMAD5, which in turn decreased cell proliferation and promoted cell apoptosis. After KGN cells were stimulated with insulin for 48 h, there was increased expression of SMAD5 protein and decreased apoptosis. Additionally, knockdown/overexpression of SMAD5 in KGN cells reduced/increased cell number and promoted/ inhibited cell apoptosis. Insulin-stimulated primary GCs isolated from PCOS patients, in contrast to normal GCs or KGN cells, did not exhibit decreased miR-27a-3p expression. The differences in the expression levels in KGN cells and human PCOS GCs are likely explained by increased miR-27a-3p expression in the GCs caused by insulin resistance in PCOS. Taken together, our data provided evidence for a functional role of miR-27a-3p in the GCs dysfunction that occurs in human PCOS patients.//////////////////
Anti-Mllerian Hormone Recruits BMPR-IA in Immature Granulosa Cells. Sdes L 2013 et al.
Anti-Mllerian hormone (AMH) is a member of the TGF- superfamily secreted by the gonads of both sexes. This hormone is primarily known for its role in the regression of the Mllerian ducts in male fetuses. In females, AMH is expressed in granulosa cells of developing follicles. Like other members of the TGF- superfamily, AMH transduces its signal through two transmembrane serine/threonine kinase receptors including a well characterized type II receptor, AMHR-II. The complete signalling pathway of AMH involving Smads proteins and the type I receptor is well known in the Mllerian duct and in Sertoli and Leydig cells but not in granulosa cells. In addition, few AMH target genes have been identified in these cells. Finally, while several co-receptors have been reported for members of the TGF- superfamily, none have been described for AMH. Here, we have shown that none of the Bone Morphogenetic Proteins (BMPs) co-receptors, Repulsive guidance molecules (RGMs), were essential for AMH signalling. We also demonstrated that the main Smad proteins used by AMH in granulosa cells were Smad 1 and Smad 5. Like for the other AMH target cells, the most important type I receptor for AMH in these cells was BMPR-IA. Finally, we have identified a new AMH target gene, Id3, which could be involved in the effects of AMH on the differentiation of granulosa cells and its other target cells.
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Ovarian localization
Primordial Germ Cell, Granulosa, Luteal cells
Comment
Effect of Anti-Müllerian hormone (AMH) and bone morphogenetic protein 15 (BMP-15) on steroidogenesis in primary-cultured human luteinizing granulosa cells through Smad5 signalling. Prapa E et al. (2015) To determine if there is any effect of AMH and BMP-15 on estradiol and progesterone production from primary-cultured human luteinizing granulosa cells, to delineate what is the effect of FSH on their actions and which are the possible mechanisms involved. Luteinizing granulosa cells (GCs), obtained from follicular fluid of 30 women undergoing in vitro fertilization, were cultured, after a short 24-h preincubation period, in serum-free medium for 24 or/and 48 h in the presence/absence of various concentrations of AMH, BMP-15 and FSH alone or in combinations. Estradiol and progesterone production, SMAD5 phosphorylation and StAR expression were studied in parallel. Steroids were measured in culture-supernatant using enzyme-immunoassays, while Smad5-signaling pathway activation and StAR protein expression were assessed immunocytochemically. We found that the treatment of AMH in GCs for 24/48 h attenuated FSH-induced estradiol production (p < 0.001), had no effect on basal estradiol levels, decreased basal progesterone production (p < 0.001) and FSH-induced StAR expression (p < 0.001). On the other hand, BMP-15 decreased basal estradiol levels (p < 0.001) and attenuated FSH-induced estradiol production (p < 0.001). Furthermore, BMP-15 reduced progesterone basal secretion (p < 0.001), an effect that was partially reversed by FSH (p < 0.01), probably via increasing StAR expression (p < 0.001). FSH-induced StAR expression was also attenuated by BMP-15 (p < 0.001). FSH, AMH and BMP-15 activated Smad-signaling pathway, as confirmed by the increase of phospo-Smad5 protein levels (p < 0.001 compared to control). AMH and BMP-15 by interacting with FSH affect the production of estradiol and progesterone from cultured luteinizing-granulosa cells possibly via Smad5-protein phosphorylation.//////////////////
Follicle stages
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment:Chang H, et al 2001 reported that Smad5 is required for mouse primordial germ cell development.
Smad5, together with Smad1 and Smad8, have been implicated as downstream
signal mediators for several bone morphogenetic proteins (BMPs). Recent studies
have shown that primordial germ cells (PGCs) are absent or greatly reduced in
Bmp4 or Bmp8b mutant mice. To define the role of Smad5 in PGC development,
the authors examined PGC number in Smad5 mutant mice by Oct4 whole-mount in situ
hybridization and alkaline phosphatase staining and found ectopic PGC-like cells
in the amnion of some Smad5 mutant mice, however, the total number of PGCs
was greatly reduced or completely absent in Smad5 mutant embryos, similar to
Bmp4 or Bmp8b mutant embryos. Therefore, Smad5 is an important factor
involved in PGC generation and localization.
Species: mouse
Mutation name: None
type: null mutation fertility: None Comment: Smad1-Smad5 Ovarian Conditional Knockout Mice Develop a Disease Profile Similar to the Juvenile Form of Human Granulosa Cell Tumors. Middlebrook BS et al. Granulosa cell tumors (GCTs) of the ovary are rare sex cord stromal tumors. Although generally indolent, GCTs recur, and if not diagnosed and treated in early stages, survival rates are significantly shortened. Very little is known regarding GCT etiology. Because of the low incidence of cases and lack of standard diagnostics, mouse models for granulosa cell tumors are a valuable tool for studying GCTs and provide models for developing diagnostic and treatment strategies. We recently developed a novel mouse model of metastatic granulosa cell tumors by genetic deletion of the bone morphogenetic protein signaling transcription factors (SMADs) in granulosa cells of the ovary. Histological and serum hormone analyses reveal that this mouse model most closely resembles the juvenile form of GCT. We further analyzed samples of human juvenile GCT (JGCT) for expression of anti-M?an hormone and activation of two major signaling pathways: TGFbeta/SMAD2/3 and wingless-related mouse mammary tumor virus integration site (Wnt)/beta-catenin. The TGFbeta family is active in mouse Smad1-Smad5 double knockout tumors, and here we show that this pathway, but not the beta-catenin pathway, is activated in samples of human JGCT. These data suggest that the SMAD family, possibly through disruption of SMAD1/5 or activation of SMAD2/3 may contribute to the pathogenesis of JGCT in humans.