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Molecular Mechanism and Function of Progesterone Receptor
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Molecular Mechanism and Function of Progesterone Receptor

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 23021

Special Issue Editor

Prof. Dr. Ozlem Guzeloglu-Kayisli

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Guest Editor
Department of Ob and Gyn, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
Interests: parturition; preterm birth; reproduction; steroid receptor regulation; signaling pathway
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In mammalian species, progesterone, steroid hormone, plays a key role in the development, and maintenance of female reproductive tissues such as uterus, ovary and mammary gland as well as plays a crucial role in non-reproductive tissues such as cardiovascular system, bone, and central nervous system, indicating the widespread role of progesterone in normal physiology. The biological activity of progesterone is mediated by binding to the progesterone receptor (PR), which belongs to the steroid hormone receptor superfamily. Two PR isoforms, PRA and PRB arise from the same gene, PGR, using alternative promoters and exhibit both overlapping and distinct transcriptional activity in tissue-specific manner. In most of cells, PRs are mainly regulated by estrogen, its regulation is not only transcriptional levels, but also subject to extensive post-transcriptional modifications including phosphorylation, acetylation, SUMOylation and ubiquitination. All these modifications alter the stability, hormone sensitivity and/or nuclear localization of both liganded and unliganded PRs.

This Special Issue of IJMS explores the transcriptional and post-transcriptional regulation of PRs, the role of its subcellular localization, classical and non-classical progesterone signaling, the role of PR coregulators in modifying progesterone action in both physiological and pathophysiological conditions. Bringing together different aspects in one issue, hopefully, will inspire researchers to study these interesting and important receptors using contemporary molecular tools.

Prof. Dr. Ozlem Guzeloglu-Kayisli
Guest Editor

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Keywords

  • progesterone
  • progesterone receptor
  • signaling pathway
  • transcriptional and posttranscriptional regulation
  • subcellular localization
  • PR isoform switch
  • reproductive tissue
  • labor
  • cancer

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Published Papers (7 papers)

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Research

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17 pages, 4047 KiB  
Article
Enhanced ZBTB16 Levels by Progestin-Only Contraceptives Induces Decidualization and Inflammation
by Sefa Arlier, Umit A. Kayisli, Nihan Semerci, Asli Ozmen, Kellie Larsen, Frederick Schatz, Charles J. Lockwood and Ozlem Guzeloglu-Kayisli
Int. J. Mol. Sci. 2023, 24(13), 10532; https://doi.org/10.3390/ijms241310532 - 23 Jun 2023
Cited by 2 | Viewed by 1867
Abstract
Progestin-only long-acting reversible-contraceptive (pLARC)-exposed endometria displays decidualized human endometrial stromal cells (HESCs) and hyperdilated thin-walled fragile microvessels. The combination of fragile microvessels and enhanced tissue factor levels in decidualized HESCs generates excess thrombin, which contributes to abnormal uterine bleeding (AUB) by inducing inflammation, [...] Read more.
Progestin-only long-acting reversible-contraceptive (pLARC)-exposed endometria displays decidualized human endometrial stromal cells (HESCs) and hyperdilated thin-walled fragile microvessels. The combination of fragile microvessels and enhanced tissue factor levels in decidualized HESCs generates excess thrombin, which contributes to abnormal uterine bleeding (AUB) by inducing inflammation, aberrant angiogenesis, and proteolysis. The- zinc finger and BTB domain containing 16 (ZBTB16) has been reported as an essential regulator of decidualization. Microarray studies have demonstrated that ZBTB16 levels are induced by medroxyprogesterone acetate (MPA) and etonogestrel (ETO) in cultured HESCs. We hypothesized that pLARC-induced ZBTB16 expression contributes to HESC decidualization, whereas prolonged enhancement of ZBTB16 levels triggers an inflammatory milieu by inducing pro-inflammatory gene expression and tissue-factor-mediated thrombin generation in decidualized HESCs. Thus, ZBTB16 immunostaining was performed in paired endometria from pre- and post-depo-MPA (DMPA)-administrated women and oophorectomized guinea pigs exposed to the vehicle, estradiol (E2), MPA, or E2 + MPA. The effect of progestins including MPA, ETO, and levonorgestrel (LNG) and estradiol + MPA + cyclic-AMP (E2 + MPA + cAMP) on ZBTB16 levels were measured in HESC cultures by qPCR and immunoblotting. The regulation of ZBTB16 levels by MPA was evaluated in glucocorticoid-receptor-silenced HESC cultures. ZBTB16 was overexpressed in cultured HESCs for 72 h followed by a ± 1 IU/mL thrombin treatment for 6 h. DMPA administration in women and MPA treatment in guinea pigs enhanced ZBTB16 immunostaining in endometrial stromal and glandular epithelial cells. The in vitro findings indicated that: (1) ZBTB16 levels were significantly elevated by all progestin treatments; (2) MPA exerted the greatest effect on ZBTB16 levels; (3) MPA-induced ZBTB16 expression was inhibited in glucocorticoid-receptor-silenced HESCs. Moreover, ZBTB16 overexpression in HESCs significantly enhanced prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP1), and tissue factor (F3) levels. Thrombin-induced interleukin 8 (IL-8) and prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA levels in control-vector-transfected HESCs were further increased by ZBTB16 overexpression. In conclusion, these results supported that ZBTB16 is enhanced during decidualization, and long-term induction of ZBTB16 expression by pLARCs contributes to thrombin generation through enhancing tissue factor expression and inflammation by enhancing IL-8 and PTGS2 levels in decidualized HESCs. Full article
(This article belongs to the Special Issue Molecular Mechanism and Function of Progesterone Receptor)
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13 pages, 2564 KiB  
Article
Progesterone Can Directly Inhibit the Life Activities of Toxoplasma gondii In Vitro through the Progesterone Receptor Membrane Component (PGRMC)
by Yihan Wu, Xiao Zhang, Yong Fu, Jing Liu, Yangfei Xue and Qun Liu
Int. J. Mol. Sci. 2022, 23(7), 3843; https://doi.org/10.3390/ijms23073843 - 31 Mar 2022
Cited by 7 | Viewed by 2298
Abstract
Toxoplasma gondii (T. gondii), as an opportunistic pathogen, has special pathogenic effects on pregnant animals and humans. Progesterone (P4) is a critical hormone that supports pregnancy, and its levels fluctuate naturally during early pregnancy. However, little is known about the association of [...] Read more.
Toxoplasma gondii (T. gondii), as an opportunistic pathogen, has special pathogenic effects on pregnant animals and humans. Progesterone (P4) is a critical hormone that supports pregnancy, and its levels fluctuate naturally during early pregnancy. However, little is known about the association of host P4 levels with the infectivity and pathogenicity of T. gondii. Our study showed that P4 significantly inhibited the invasion and proliferation of tachyzoites, resulting in abnormal cytoskeletal daughter budding and subsequent autophagy in vitro. To investigate the underlying mechanism, we identified a Toxoplasma gondii progesterone membrane receptor protein (TgPGRMC) that was localized to the mitochondrion and closely related to the effect of P4 on tachyzoites. The knockout of the pgrmc gene conferred resistance to P4 inhibitory effects. Our results prove the direct relationship between P4 single factors and T. gondii in vitro and demonstrate that TgPGRMC is an important link between T. gondii and P4, providing a new direction for research on T. gondii infection during pregnancy. Full article
(This article belongs to the Special Issue Molecular Mechanism and Function of Progesterone Receptor)
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14 pages, 2888 KiB  
Article
Single-Oocyte Gene Expression Suggests That Curcumin Can Protect the Ovarian Reserve by Regulating the PTEN-AKT-FOXO3a Pathway
by Yue Lv, Rui-Can Cao, Hong-Bin Liu, Xian-Wei Su, Gang Lu, Jin-Long Ma and Wai-Yee Chan
Int. J. Mol. Sci. 2021, 22(12), 6570; https://doi.org/10.3390/ijms22126570 - 18 Jun 2021
Cited by 18 | Viewed by 3666
Abstract
A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single [...] Read more.
A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation. Full article
(This article belongs to the Special Issue Molecular Mechanism and Function of Progesterone Receptor)
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Graphical abstract

10 pages, 978 KiB  
Article
Cyclic Adenosine Monophosphate Eliminates Sex Differences in Estradiol-Induced Elastin Production from Engineered Dermal Substitutes
by Andreja Moset Zupan, Carolyn Nietupski and Stacey C. Schutte
Int. J. Mol. Sci. 2021, 22(12), 6358; https://doi.org/10.3390/ijms22126358 - 14 Jun 2021
Cited by 5 | Viewed by 1975
Abstract
Lack of adult cells’ ability to produce sufficient amounts of elastin and assemble functional elastic fibers is an issue for creating skin substitutes that closely match native skin properties. The effects of female sex hormones, primarily estrogen, have been studied due to the [...] Read more.
Lack of adult cells’ ability to produce sufficient amounts of elastin and assemble functional elastic fibers is an issue for creating skin substitutes that closely match native skin properties. The effects of female sex hormones, primarily estrogen, have been studied due to the known effects on elastin post-menopause, thus have primarily included older mostly female populations. In this study, we examined the effects of female sex hormones on the synthesis of elastin by female and male human dermal fibroblasts in engineered dermal substitutes. Differences between the sexes were observed with 17β-estradiol treatment alone stimulating elastin synthesis in female substitutes but not male. TGF-β levels were significantly higher in male dermal substitutes than female dermal substitutes and the levels did not change with 17β-estradiol treatment. The male dermal substitutes had a 1.5-fold increase in cAMP concentration in the presence of 17β-estradiol compared to no hormone controls, while cAMP concentrations remained constant in the female substitutes. When cAMP was added in addition to 17β-estradiol and progesterone in the culture medium, the sex differences were eliminated, and elastin synthesis was upregulated by 2-fold in both male and female dermal substitutes. These conditions alone did not result in functionally significant amounts of elastin or complete elastic fibers. The findings presented provide insights into differences between male and female cells in response to female sex steroid hormones and the involvement of the cAMP pathway in elastin synthesis. Further explorations into the signaling pathways may identify better targets to promote elastic fiber synthesis in skin substitutes. Full article
(This article belongs to the Special Issue Molecular Mechanism and Function of Progesterone Receptor)
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15 pages, 2766 KiB  
Article
CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer
by Ashwini Makhale, Devathri Nanayakkara, Prahlad Raninga, Kum Kum Khanna and Murugan Kalimutho
Int. J. Mol. Sci. 2021, 22(11), 5782; https://doi.org/10.3390/ijms22115782 - 28 May 2021
Cited by 17 | Viewed by 3605
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of [...] Read more.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium. Full article
(This article belongs to the Special Issue Molecular Mechanism and Function of Progesterone Receptor)
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13 pages, 4254 KiB  
Article
Cell–Cell Communication at the Embryo Implantation Site of Mouse Uterus Revealed by Single-Cell Analysis
by Yi Yang, Jia-Peng He and Ji-Long Liu
Int. J. Mol. Sci. 2021, 22(10), 5177; https://doi.org/10.3390/ijms22105177 - 13 May 2021
Cited by 11 | Viewed by 4063
Abstract
As a crucial step for human reproduction, embryo implantation is a low-efficiency process. Despite rapid advances in recent years, the molecular mechanism underlying embryo implantation remains poorly understood. Here, we used the mouse as an animal model and generated a single-cell transcriptomic atlas [...] Read more.
As a crucial step for human reproduction, embryo implantation is a low-efficiency process. Despite rapid advances in recent years, the molecular mechanism underlying embryo implantation remains poorly understood. Here, we used the mouse as an animal model and generated a single-cell transcriptomic atlas of embryo implantation sites. By analyzing inter-implantation sites of the uterus as control, we were able to identify global gene expression changes associated with embryo implantation in each cell type. Additionally, we predicted signaling interactions between uterine luminal epithelial cells and mural trophectoderm of blastocysts, which represent the key mechanism of embryo implantation. We also predicted signaling interactions between uterine epithelial-stromal crosstalk at implantation sites, which are crucial for post-implantation development. Our data provide a valuable resource for deciphering the molecular mechanism underlying embryo implantation. Full article
(This article belongs to the Special Issue Molecular Mechanism and Function of Progesterone Receptor)
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Review

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21 pages, 1641 KiB  
Review
What Do We Know about Classical and Non-Classical Progesterone Receptors in the Human Female Reproductive Tract? A Review
by Yassmin Medina-Laver, Cristina Rodríguez-Varela, Stefania Salsano, Elena Labarta and Francisco Domínguez
Int. J. Mol. Sci. 2021, 22(20), 11278; https://doi.org/10.3390/ijms222011278 - 19 Oct 2021
Cited by 25 | Viewed by 4288
Abstract
The progesterone hormone regulates the human menstrual cycle, pregnancy, and parturition by its action via the different progesterone receptors and signaling pathways in the female reproductive tract. Progesterone actions can be exerted through classical and non-classical receptors, or even a combination of both. [...] Read more.
The progesterone hormone regulates the human menstrual cycle, pregnancy, and parturition by its action via the different progesterone receptors and signaling pathways in the female reproductive tract. Progesterone actions can be exerted through classical and non-classical receptors, or even a combination of both. The former are nuclear receptors whose activation leads to transcriptional activity regulation and thus in turn leads to slower but long-lasting responses. The latter are composed of progesterone receptors membrane components (PGRMC) and membrane progestin receptors (mPRs). These receptors rapidly activate the appropriate intracellular signal transduction pathways, and they can subsequently initiate specific cell responses or even modulate genomic cell responses. This review covers our current knowledge on the mechanisms of action and the relevance of classical and non-classical progesterone receptors in female reproductive tissues ranging from the ovary and uterus to the cervix, and it exposes their crucial role in female infertility. Full article
(This article belongs to the Special Issue Molecular Mechanism and Function of Progesterone Receptor)
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