Follicle-stimulating Hormone Regulates Pro-apoptotic Protein Bcl-2-interacting Mediator of Cell Death-Extra Long (BimEL)-induced Porcine Granulosa Cell Apoptosis

Wang, Xian Long; Wu, Yi; Tan, Lu; Tian, Zhen; Liu, Jing Hao; Zhu, De Sheng; Zeng, Shen Ming

doi:10.1074/jbc.m111.293274

Cited by 63 publications

(65 citation statements)

References 47 publications

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“…In sum, we have identified a pathway by which FSH-stimulated PKA hijacks GAB2 and IRS-1 to activate the PI3K pathway in GCs, leading to enhanced proliferation, inhibition of apoptosis, enhanced translation, and activation of target genes with products that define the mature, preovulatory GC (3)(4)(5)(6)(7)(8)(9). Our results reveal a previously unknown function for GAB2 as a multifactorial adaptor downstream of a GPCR and PKA.…”

Section: Discussionmentioning

confidence: 72%

“…Consistent with a tumorigenic model, FSH-stimulated AKT activation promotes enhanced HIF-1 activity, leading to expression of VEGF (48) and cell survival (8). There is also a wealth of data linking GAB2 with tumorigenesis (reviewed in ref.…”

Section: Discussionmentioning

confidence: 74%

“…AKT-stimulated phosphorylation of FOXO1 releases repressive actions of the transcriptional factor on a number of FSH target genes, including cyclin D2, aromatase, epiregulin, P450scc, and inhibin-α (5), as well as genes involved in the cholesterol biosynthetic pathway (9). AKT also signals to inhibit apoptosis, in part, by phosphorylation of FOXO3a to inhibit expression of the proapoptotic protein Bim-extra long (Bcell lymphoma-2 interacting modulator of cell death) (8).…”

mentioning

confidence: 99%

“…Studies using dominant negative and constitutively active AKT showed that the AKT pathway is necessary but not sufficient for activation of many key FSH target genes, including the LH receptor, 3β-hydroxysteroid dehydrogenase, aromatase, and inhibin-a (3). AKT targets in GCs include tuberin (4), forkhead box O factor 1 (FOXO1) (5-7), and FOXO3a (8). Phosphorylation and inactivation of tuberin enhances signaling through mammalian target of rapamycin complex 1 (mTORC1)/regulatory-associated protein of mTOR to enhance translation of several proteins in GCs, including the transcriptional activator hypoxia inducible factor-1α (HIF-1α) (4).…”

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confidence: 99%

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PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells

Hunzicker-Dunn

Lopez-Biladeau

Law

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

120

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Controlled maturation of ovarian follicles is necessary for fertility. Follicles are restrained at an immature stage until stimulated by FSH secreted by pituitary gonadotropes. FSH acts on granulosa cells within the immature follicle to inhibit apoptosis, promote proliferation, stimulate production of steroid and protein hormones, and induce ligand receptors and signaling intermediates. The phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) pathway is a pivotal signaling corridor necessary for transducing the FSH signal. We report that protein kinase A (PKA) mediates the actions of FSH by signaling through multiple targets to activate PI3K/AKT. PKA uses a route that promotes phosphorylation of insulin receptor substrate-1 (IRS-1) on Tyr 989, a canonical binding site for the 85-kDa regulatory subunit of PI3K that allosterically activates the catalytic subunit. PI3K activation leads to activation of AKT through phosphorylation of AKT on Thr 308 and Ser 473. The adaptor growth factor receptor bound protein 2-associated binding protein 2 (GAB2) is present in a preformed complex with PI3K heterodimer and IRS-1, it is an A-kinase anchoring protein that binds the type I regulatory subunit of PKA, and it is phosphorylated by PKA on Ser 159. Overexpression of GAB2 enhances FSHstimulated AKT phosphorylation. GAB2, thus, seems to coordinate signals from the FSH-stimulated rise in cAMP that leads to activation of PI3K/AKT. The ability of PKA to commandeer IRS-1 and GAB2, adaptors that normally integrate receptor/nonreceptor tyrosine kinase signaling into PI3K/AKT, reveals a previously unrecognized route for PKA to activate a pathway that promotes proliferation, inhibits apoptosis, enhances translation, and initiates differentiation of granulosa cells. F ertility in females requires controlled maturation of the oocyte and supporting theca and granulosa cells (GCs) that comprise the ovarian follicle. Follicles are restrained at the preantral stage until they are stimulated by FSH synthesized and secreted from pituitary gonadotropes. FSH directs GCs to proliferate and produce steroid hormones, such as estrogen and progesterone, protein hormones, including inhibin, and growth factors, such as VEGF. These hormones and growth factors not only regulate oocyte maturation and support the growth and differentiation of follicles but also regulate uterine receptivity and provide feedback to the hypothalamus and pituitary (reviewed in ref. 1). In response to FSH, follicles develop to a mature preovulatory stage competent to receive the surge of luteinizing hormone (LH) that promotes ovulation and terminal differentiation of GCs and theca cells to luteal cells.FSH signals through its surface G protein-coupled receptor (GPCR) localized to GCs (2). A crucial pathway by which FSH signals is the PI3K pathway that leads to the phosphorylation and activation of the nodal kinase AKT (protein kinase B). Studies using dominant negative and constitutively active AKT showed that the AKT pathway is necessary but not sufficient for activation of...

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 74%

mentioning

confidence: 99%

mentioning

confidence: 99%

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PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells

Hunzicker-Dunn

Lopez-Biladeau

Law

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

120

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“…Moreover, Wang et al . reported Bim induces porcine follicular atresia [46]. qRT–PCR analysis revealed the increased expression of Bim in the ovaries of miR-17-92 cKO female mice, suggesting that Bim acts as the target gene of miR-17-92 in cKO mice ovaries, contributing to follicular atresia.…”

Section: Discussionmentioning

confidence: 99%

Ablation of the MiR-17-92 MicroRNA Cluster in Germ Cells Causes Subfertility in Female Mice

Wang

Tian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Oogenesis is a highly complex process that is intricately regulated by interactions of multiple genes and signaling molecules. However, the underlying molecular mechanisms are poorly understood. There is emerging evidence that microRNAs contribute to oogenesis. Here, we aimed to investigate the role of miR-17-92 cluster in regulating oogenesis. Methods: The miR-17-92 cluster was genetically ablated in germ cells of female mice by applying the Cre-loxp system for conditional gene knockout. Mating experiment, superovulation and histological analysis were used to assess the fertility of the model female mice. TUNEL assay was used to identify apoptotic cells in ovaries. The expression level of apoptosis- and follicular atresia- related genes was evaluated by qRT-PCR. Western blotting was performed to detect protein expression. Bioinformatics software and dual luciferase reporter assay were applied to predict and verify the target of miR-17-92 cluster. Results: Deletion of miR-17-92 cluster in germ cells of female mice caused increased oocyte degradation and follicular atresia, perturbed oogenesis, and ultimately led to subfertility. Genes involved in follicular atresia and the mitochondrial apoptotic pathway were obviously up-regulated. Furthermore, we verified that miR-19a regulated oogenesis at the post-transcriptional level by targeting Bmf in the ovaries of miR-17-92 cluster conditional knockout female mice. Conclusion: The miR-17-92 cluster is an important regulator of oogenesis. These findings will assist in better understanding the etiology of disorders in oogenesis and in developing new therapeutic targets for female infertility.

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A Mutation Losing an RBP‐Binding Site in the LncRNA NORSF Transcript Influences Granulosa Cell Apoptosis and Sow Fertility

Wang,

Sheng,

Zhang

et al. 2024

Advanced Science

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Sow fertility is an economically important quantitative trait. Hundreds of quantitative trait loci (QTLs) containing tens of thousands of potential candidate genes are excavated. However, among these genes, non‐coding RNAs including long non‐coding RNAs (lncRNAs) are often overlooked. Here, it is reported that NORSF is a novel causal lncRNA for sow fertility traits in QTLs. QTLs are characterized for sow fertility traits at the genome‐wide level and identified 4,630 potential candidate lncRNAs, with 13 differentially expressed during sow follicular atresia. NORSF, a lncRNA that involved in sow granulosa cell (sGC) function, is identified as a candidate gene for sow fertility traits as a G to A transversion at 128 nt in its transcript is shown to be markedly associated with sow fertility traits. Mechanistically, after forming the RNA:dsDNA triplexes with the promoter of Caspase8, NORSF transcript with allele G binds to an RNA‐binding protein (RBP) NR2C1 and recruits it to the promoter of Caspase8, to induce Caspase8 transcription in sGCs. Functionally, this leads to a loss of inducing effect of NORSF on sGC apoptosis by inactivating the death receptor‐mediated apoptotic pathway. This study identified a novel causal lncRNA that can be used for the genetic improvement of sow fertility traits.

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Follicle-stimulating Hormone Regulates Pro-apoptotic Protein Bcl-2-interacting Mediator of Cell Death-Extra Long (BimEL)-induced Porcine Granulosa Cell Apoptosis

Cited by 63 publications

References 47 publications

PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells

PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells

Ablation of the MiR-17-92 MicroRNA Cluster in Germ Cells Causes Subfertility in Female Mice

A Mutation Losing an RBP‐Binding Site in the LncRNA NORSF Transcript Influences Granulosa Cell Apoptosis and Sow Fertility

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