ArticleJournal of ovarian research2020
STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells.
Article in Journal of ovarian research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 17 citations in OpenAlex.
- Digitoxin-induced apoptosis in ovarian granulosa cells disrupts follicular development and impairs reproductive performance.Journal of ovarian research · 2026Article
- Disruption of ovarian function and induction of apoptosis in female mice by Brefeldin A: Mechanistic insights into reproductive toxicity.Animal models and experimental medicine · 2025Article
- Celastrol modulates IRS1 expression to alleviate ovarian aging and to enhance follicular development.Cell biology and toxicology · 2025Article
- Cytotoxic effects of five Iranian medicinal plants on pancreatic cancer cell lines and investigation of induced changes in the expression of several key genes.BMC complementary medicine and therapies · 2025Article
- PSAT1 regulated by STAT4 enhances the proliferation, invasion and migration of ovarian cancer cells via the PI3K/AKT pathway.International journal of molecular medicine · 2025Article
- DNA Methylation Mediates the Transcription ofCells · 2025Article
- Effects of STAT4 on myocardial ischemia‑reperfusion injury and the underlying mechanisms.Molecular medicine reports · 2024Article
- STAT4-Mediated Klotho Up-Regulation Contributes to the Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning via Inhibiting Neuronal Pyroptosis.Molecular neurobiology · 2024Article
- Follicular fluid meiosis-activating sterol prevents porcine ovarian granulosa cells from hypoxia-induced apoptosis via inhibiting STAT4 expression.Journal of animal science · 2024Article
- A risk model developed based on necroptosis to assess progression for ischemic cardiomyopathy and identify possible therapeutic drugs.Frontiers in pharmacology · 2022Article
- Modulation of Cathepsin S (Animals : an open access journal from MDPI · 2021Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundIn mammals, it is known that the estradiol-17β (E2) is mainly synthetized in ovarian granulosa cells (GCs), and the excessive apoptosis of GCs induces the follicular atresia. Many studies have implicated the essential role of KISS1, with the pro-synthetic effect of E2 and the anti-apoptotic effect on GCs, in the mammalian folliculogenesis, and several STAT4 potential binding sites were previously predicted on the promoter of KISS1 in pigs. However, the biological effects of STAT4 on GCs and the molecular regulation between STAT4 and KISS1 remained largely unknown.
methodsUsing the porcine GCs as the cellular model, the overexpression plasmid, small interfering RNA, 5'-deletion and luciferase assay were applied to investigate the molecular mechanisms for STAT4 regulating the expression of KISS1.
resultsIn this study, the STAT4 negatively regulated the mRNA and protein levels of KISS1 in porcine GCs, and the mRNA level of STAT4 was observed to significantly decrease from immature to mature follicles, which was inversed with that of KISS1. The relative luciferase activity of KISS1 promoter was significantly increased with deletion of the fourth potential binding site (- 305/- 295), and ChIP further confirmed that the STAT4 bound at - 305/- 295 region of KISS1. Besides, the STAT4 significantly regulated the mRNA levels of PDK1, FOXO3 and TSC2 of PI3K signaling pathway to promote the cell apoptosis and the percentage of cells at G0/G1 phase of cell cycle in GCs. Alternatively, the STAT4 significantly decreased the mRNA levels of CYP17, 3B-HSD, 17B-33 HSD, ESR1, and ESR2, as well as the concentration of E2 in GCs. Furthermore, interfering with the expression of STAT4 was observed to significantly stimulate the pro-synthetic effect of E2 and anti-apoptotic effect of KISS1 in GCs.
conclusionsCollectively, the STAT4 might directly target at - 305/- 295 region of KISS1 to negatively regulate the transcription of KISS1, promote the cell apoptosis via PI3K signaling pathway, suppress the synthesis of E2 through the estrogen signaling pathway in porcine GCs. These proposed works could provide useful insight in further investigations on the molecular functionalities of STAT4 and KISS1 in the folliculogenesis of mammals.
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