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The FOS/AP-1 Regulates Metabolic Changes and Cholesterol Synthesis in Human Periovulatory Granulosa Cells.
- Source :
-
Endocrinology [Endocrinology] 2021 Sep 01; Vol. 162 (9). - Publication Year :
- 2021
-
Abstract
- FOS, a subunit of the activator protein-1 (AP-1) transcription factor, has been implicated in various cellular changes. In the human ovary, the expression of FOS and its heterodimeric binding partners JUN, JUNB, and JUND increases in periovulatory follicles. However, the specific role of the FOS/AP-1 remains elusive. The present study determined the regulatory mechanisms driving the expression of FOS and its partners and functions of FOS using primary human granulosa/lutein cells (hGLCs). Human chorionic gonadotropin (hCG) induced a biphasic increase in the expression of FOS, peaking at 1 to 3 hours and 12 hours. The levels of JUN proteins were also increased by hCG, with varying expression patterns. Coimmunoprecipitation analyses revealed that FOS is present as heterodimers with all JUN proteins. hCG immediately activated protein kinase A and p42/44MAPK signaling pathways, and inhibitors for these pathways abolished hCG-induced increases in the levels of FOS, JUN, and JUNB. To identify the genes regulated by FOS, high-throughput RNA sequencing was performed using hGLC treated with hCG ± T-5224 (FOS inhibitor). Sequencing data analysis revealed that FOS inhibition affects the expression of numerous genes, including a cluster of genes involved in the periovulatory process such as matrix remodeling, prostaglandin synthesis, glycolysis, and cholesterol biosynthesis. Quantitative PCR analysis verified hCG-induced, T-5224-regulated expression of a selection of genes involved in these processes. Consistently, hCG-induced increases in metabolic activities and cholesterol levels were suppressed by T-5224. This study unveiled potential downstream target genes of and a role for the FOS/AP-1 complex in metabolic changes and cholesterol biosynthesis in granulosa/lutein cells of human periovulatory follicles.<br /> (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Cells, Cultured
Chorionic Gonadotropin pharmacology
Energy Metabolism drug effects
Female
Gene Expression Regulation drug effects
Granulosa Cells drug effects
Humans
Ovulation drug effects
Ovulation genetics
Ovulation metabolism
Proto-Oncogene Proteins c-fos drug effects
Proto-Oncogene Proteins c-jun drug effects
Proto-Oncogene Proteins c-jun genetics
Proto-Oncogene Proteins c-jun metabolism
Time Factors
Transcription Factor AP-1 drug effects
Transcription Factor AP-1 physiology
Cholesterol biosynthesis
Energy Metabolism genetics
Granulosa Cells metabolism
Proto-Oncogene Proteins c-fos physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7170
- Volume :
- 162
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 34171102
- Full Text :
- https://doi.org/10.1210/endocr/bqab127