STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells
Abstract Background In 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 ant...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-11-01
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| Series: | Journal of Ovarian Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13048-020-00741-5 |
| _version_ | 1797972642344468480 |
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| author | Yao Jiang Xiaoping Xin Xiangchun Pan Ailing Zhang Zhe Zhang Jiaqi Li Xiaolong Yuan |
| author_facet | Yao Jiang Xiaoping Xin Xiangchun Pan Ailing Zhang Zhe Zhang Jiaqi Li Xiaolong Yuan |
| author_sort | Yao Jiang |
| collection | DOAJ |
| description | Abstract Background In 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. Methods Using 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. Results In 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. Conclusions Collectively, 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. |
| first_indexed | 2024-04-11T03:51:42Z |
| format | Article |
| id | doaj.art-29035255f164429581fe9063bb75df17 |
| institution | Directory Open Access Journal |
| issn | 1757-2215 |
| language | English |
| last_indexed | 2024-04-11T03:51:42Z |
| publishDate | 2020-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Ovarian Research |
| spelling | doaj.art-29035255f164429581fe9063bb75df172023-01-02T01:50:29ZengBMCJournal of Ovarian Research1757-22152020-11-0113111210.1186/s13048-020-00741-5STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cellsYao Jiang0Xiaoping Xin1Xiangchun Pan2Ailing Zhang3Zhe Zhang4Jiaqi Li5Xiaolong Yuan6Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural UniversityGuangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural UniversityGuangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural UniversityCollege of Biology and Food Engineering/Development, Center of Applied Ecology and Ecological Engineering in Universities, Guangdong University of EducationGuangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural UniversityGuangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural UniversityGuangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, National Engineering Research Centre for Breeding Swine Industry, College of Animal Science, South China Agricultural UniversityAbstract Background In 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. Methods Using 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. Results In 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. Conclusions Collectively, 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.http://link.springer.com/article/10.1186/s13048-020-00741-5STAT4KISS1Cell apoptosisSynthesis of E2Ovarian granulosa cells |
| spellingShingle | Yao Jiang Xiaoping Xin Xiangchun Pan Ailing Zhang Zhe Zhang Jiaqi Li Xiaolong Yuan STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells Journal of Ovarian Research STAT4 KISS1 Cell apoptosis Synthesis of E2 Ovarian granulosa cells |
| title | STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells |
| title_full | STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells |
| title_fullStr | STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells |
| title_full_unstemmed | STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells |
| title_short | STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells |
| title_sort | stat4 targets kiss1 to promote the apoptosis of ovarian granulosa cells |
| topic | STAT4 KISS1 Cell apoptosis Synthesis of E2 Ovarian granulosa cells |
| url | http://link.springer.com/article/10.1186/s13048-020-00741-5 |
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