The FOS/AP-1 regulates metabolic changes and cholesterol synthesis in human periovulatory granulosa cells

Yohan Choi, Hayce Jeon, James W. Akin, Thomas E. Curry, Misung Jo

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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-5224regulated 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.

Original languageEnglish
Article numberbqab127
JournalEndocrinology
Volume162
Issue number9
DOIs
StatePublished - Sep 2021

Bibliographical note

Funding Information:
This research was supported by the Lalor Foundation Postdoctoral Fellowship (Y.C.), the National Institutes of Health grants, P01HD71875 (M.J. and T.E.C.), R03HD095098 (M.J.), and R01HD096077 (M.J.). The seahorse glycolytic stress test was supported by the Redox Metabolism Shared Facility of the University of Kentucky Markey Cancer Center (P30CA177558).

Publisher Copyright:
© The Author(s) 2021.

Keywords

  • FOS
  • Granulosa cells
  • Human
  • JUN proteins
  • Ovulation

ASJC Scopus subject areas

  • Endocrinology

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