| transforming growth factor beta 1 | OKDB#: 76 |
| Symbols: | TGFB1 | Species: | human | ||
| Synonyms: | CED, LAP, DPD1, TGFB, IBDIMDE, TGFbeta, TGF-beta1 | Locus: | 19q13.2 in Homo sapiens |
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| General Comment |
TGF-beta is a 25kDa homodimeric protein. It belongs to the TGF-beta superfamily sharing a similar cysteine-knot structure. Five different isoforms have been described of which TGF-beta 1-3 are found in several mammalian tissues. In the ovary TGF-beta 1 and 2 have been described. General functions of TGF-beta include modulation of cell cycles, mesenchymal-epithelial interactions, extracellular matrix and other peptide growth factors./////Altered Expression of Transforming Growth Factor-Beta Isoforms in Bovine Cystic Ovarian Disease. Matiller V 2014 et al.
Cystic ovarian disease (COD) is one of the main causes of infertility in dairy cattle. It has been shown that intra-ovarian factors may contribute to follicular persistence. Transforming growth factor-beta (TGFB) isoforms are important paracrine and autocrine signalling molecules that regulate ovarian follicle growth and physiology. Considering the importance of these factors in the ovarian physiology, in this study, we examined the expression of TGFB isoforms (TGFB1, TGFB2 and TGFB3) in the ovary of healthy cows and animals with spontaneous and adrenocorticotrophic hormone (ACTH)-induced COD. In the oestrous-synchronized control group, the expression of TGFB1 in granulosa and theca cells was higher in spontaneous cysts than in atretic or tertiary follicles. When we compared TGFB2 expression in granulosa cells from atretic or tertiary follicles from the oestrous-synchronized control group with that in ACTH-induced or spontaneous follicular cysts, we found a higher expression in the latter. The expression of the TGFB isoforms studied was also altered during folliculogenesis in both the spontaneous and ACTH-induced COD groups. As it has been previously shown that TGFB influences steroidogenesis, ovarian follicular proliferation and apoptosis, an alteration in its expression may contribute to the pathogenesis of this disease.
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NCBI Summary: This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016] |
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| General function | Ligand, Growth factor, Cell death/survival, Apoptosis, Cell cycle regulation, DNA Replication | ||||
| Comment | Transforming growth factor-beta (TGF-beta) is a potent antimitogen in a wide variety of cells and is postulated to inhibit cell cycle progression by blocking the late G1 activation of the cdks, thereby preventing pRb phosphorylation and S phase entry (Saltis, 1996; Koff et al., 1993). Both TGF-beta 1 and 2 significantly increased follicular thymidine incorporation in a dose-dependent manner; the effect was greater for small preantral follicles, such as those of stages 1-4 (Roy, 1993). Subconfluent cultures treated with TGF alpha or TGF beta 1 alone remained healthy whereas in the presence of both TGF alpha and TGF beta 1 there was light microscopical evidence of rounding up of cells and detachment from the monolayer (Foghi et al, 1997). DNA synthesis in rat granulosa cells is dependent on the presence of TGF-beta. In the presence of TGF-beta, FSH or SIP, acting through cAMP-dependent and cAMP-independent mechanisms respectively, can recruit more cells to enter the cell cycle and initiate DNA synthesis (Khan et al, 1992). | ||||
| Cellular localization | Secreted | ||||
| Comment | candidate123 | ||||
| Ovarian function | Follicle development, Initiation of primordial follicle growth, Antral follicle growth, Steroid metabolism | ||||
| Comment | The p38 signaling pathway mediates the TGF-β1-induced increase in type I collagen deposition in human granulosa cells. Li H et al. (2020) Type I collagen, which is mainly composed of collagen type I alpha 1 chain (COL1A1), is the most abundant extracellular matrix (ECM) protein in the mammalian ovary; and the cyclical remodeling of the ECM plays an essential role in the regulation of corpus luteum formation. Our previous studies have demonstrated that TGF-β1 is a potent inhibitor of luteinization in human granulosa-lutein (hGL) cells. Whether TGF-β1 can regulate the expression of COL1A1 during the luteal phase remains to be elucidated. The aim of this study was to investigate the effect of TGF-β1 on the regulation of COL1A1 expression and the underlying molecular mechanisms using an immortalized hGL cell line (SVOG cells) and primary hGL cells (obtained from 20 consenting patients undergoing IVF treatment). The results showed that TGF-β1 significantly upregulated the expression of COL1A1. Using inhibition approaches, including pharmacological inhibition (a specific p38 inhibitor, SB203580, and a specific ERK1/2 inhibitor, U0126) and specific siRNA-mediated knockdown inhibition, we demonstrated that TGF-β1 promoted the expression and production of COL1A1 in hGL cells, most likely via the ALK5-mediated p38 signaling pathway. Our findings provide insights into the molecular mechanisms by which TGF-β1 promotes the deposition of type I collagen during the late follicular phase in humans.//////////////////Transforming growth factor-?signaling participates in the maintenance of the primordial follicle pool in the mouse ovary. Wang ZP 2014 et al. Physiologically, only a few primordial follicles are activated to enter the growing follicle pool each wave. Recent studies in knockout mice show that early follicular activation depends on signaling from the tuberous sclerosis complex (TSC), the mammalian target of rapamycin complex 1 (mTORC1), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and phosphatidylinositol 3 kinase (PI3K) pathways. However, the manner in which these pathways are normally regulated, and whether or not TGF-?acts on them are poorly understood. So, this study aims to identify whether or not TGF-?acts on the process. Ovary organ culture experiments showed that the culture of 18.5-days post-coitus (dpc) ovaries with TGF-? reduced the total population of oocytes and activated follicles, accelerated oocyte growth was observed in ovaries treated with TGF-?1 inhibitor 2-(5-Chloro-2-fluorophenyl)pteridin-4-yl]pyridin-4-yl-amine (SD208) compared to control ovaries, the downregulation of TGF-?1 gene expression also activated early primordial follicle oocyte growth. We further showed that there was dramatically more proliferation of granulosa cells in SD208-treated ovaries and less proliferation in TGF-?-treated ovaries. Western blot and morphological analyses indicated that TGF-?signaling manipulated primordial follicle growth through TSC/mTORC1 signaling in oocytes, and the mTORC1-specific inhibitor rapamycin could partially reverse the stimulated effect of SD208 on the oocyte growth and decreased the numbers of growing follicles. In conclusion, our results suggest that TGF-?signaling plays an important physiological role in the maintenance of the dormant pool of primordial follicles, which functions through activation of p70 S6 kinase 1 (S6K1)/ribosomal protein S6 (rpS6) signaling in mouse ovaries. ///////////////////////// TGFbeta caused a significant increase in follicular diameter and estradiol and immunoreactive inhibin secretion in adult mice in a dose-related manner, but did not affect the size of preantral follicles from immature mice (Liu et al., 1999). Of several growth factors studied, only transforming growth factor-beta 1 (TGF-beta 1) stimulated HA synthesis in both mural granulosa and cumulus cells (Salustri et al., 1990). In contrast, supplement-mediated optimization of ovarian androgen biosynthesis revealed TGFbeta 1 to be a highly potent inhibitor of hCG hormonal action (Hernandez et al., 1990). | ||||
| Expression regulated by | FSH, LH, Steroids, IGF-I | ||||
| Comment | LH inhibited TGF beta secretion. IGF-I inhibited active but not total TGF beta. E2 inhibited both active (57%) and total (37%) TGF beta secretion (Magoffin et al, 1995). FSH did not influence ovarian TGF-beta 1 activity. Treatment with FSH, however, induced a massive increase in TGF-beta 2 immunoreactivity in the granulosa cells of newly developed antral and preantral follicles but not in the interstitial cells; LH, on the other hand, had no significant effect on TGF-beta 2 activity (Roy et al., 1992). Mulheron and Schomberg (1990) demonstrate that rat granulosa cells express TGF-beta 2 mRNA which is regulatable by FSH in vitro. Theca/interstitial cell expression of TGF beta 2, but not TGF beta 1, mRNA is regulated by hCG in vitro (Mulheron et al, 1991) | ||||
| Ovarian localization | Granulosa, Theca, Luteal cells | ||||
| Comment | At the time of antrum formation in the follicle, intense staining for TGF-beta 1 was observed in thecal cells. Around the preovulatory stage of development, TGF-beta 1 and TGF-beta 2 immunoreactivity was also found in the granulosa cells. In the corpus luteum, intense staining for TGF-beta 1 was found in some areas, whereas other areas were negative (Teerds and Dorrington, 1992). Species differences: In contrast to rat granulosa cells (GC), GC of the pig and cow produce very low levels of transforming growth factor-beta (TGF-beta)-like activity in vitro. Enzyme-linked immunosorbent assay analysis of porcine GC conditioned medium confirmed the presence of TGF-beta 1 at very low levels. TGF-beta 2 was undetectable (Mulheron et al., 1992). | ||||
| Follicle stages | Primordial, Primary, Secondary, Antral, Preovulatory | ||||
| Comment | Chegini et al. (1992) show that human ovarian tissue at all the reproductive states locally produces TGF-beta 1 and TGF-beta 2, and although TGF-beta 1 is present in most major ovarian cell types, TGF-beta 2 is only produced by theca cells in the follicles and small luteal cells in luteal tissues. Transforming growth factor-beta isoform expression during bovine ovarian antral follicle development. Nilsson EE, et al 2003 . Transforming growth factor-beta (TGF-beta) isoforms are important paracrine and autocrine signaling molecules for the regulation of ovarian follicle growth and physiology. Effective communication between the epithelial granulosa cells, the mesenchymal theca cells, and the oocyte is vital for ovarian function and reproductive success. The expression, localization, and regulation of TGF-beta isoforms in the developing bovine follicle was examined using both immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (RT-PCR) procedures. TGF-beta1 protein was found to be present in the granulosa cells of early pre-antral, early antral, and 1-2 mm follicles. Interestingly, there was no visible staining of granulosa cells of 3-5 or 5-10 mm follicles. There was also no TGF-beta1 staining of theca cells. TGF-beta2 and TGF-beta3 staining were present in the granulosa and theca cells of all follicle stages examined. The levels of TGF-beta mRNA expression in granulosa and theca cells from antral follicles was measured using quantitative RT-PCR. For each isoform mRNA expression levels did not change in different sized antral follicles. TGF-beta3 mRNA levels were much higher than those of TGF-beta1 and TGF-beta2 in both granulosa and theca. Expression levels were higher in theca than in granulosa for TGF-beta2 and TGF-beta3. FSH was found to decrease TGF-beta1 mRNA expression in granulosa cells, but had no effect on TGF-beta2 and TGF-beta3. Bovine ovarian follicles were found to have a unique pattern of TGF-beta isoform expression and regulation when compared to other species (i.e., rodent, pig, quail, and human). The similarities and differences between the various species is discussed to help elucidate common functions of TGF-beta in the ovary. In summary, observations demonstrate that as antral follicles develop, TGF-beta3 is the most abundant TGF-beta isoform and TGF-beta1 protein levels decline in large follicles. Granulosa cell TGF-beta1 expression was decreased by FSH and this correlated with reduced levels in large antral follicles. TGF-betas involved in antral follicular growth and development appear to act as paracrine/autocrine signaling molecules having a species-specific pattern of expression. TGF beta 1 is present in the somatic cells which are the precursors of granulosa cells, at the time of their organization in primordial follicle (Levacher et al., 1996) | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
4 mutations
Species: mouse
Species: mouse
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | July 13, 1999, midnight | by: |
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| last update: | Oct. 10, 2020, 7:52 a.m. | by: | hsueh email: |
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