Role of Progesterone Receptor Membrane Component-1 (PGRMC-1) on Bovine Oocyte Maturation.

Progesterone (P4) is cytoprotective in various experimental models, but our understanding of the mechanisms involved is still incomplete. Our laboratory has implicated brain-derived neurotrophic factor (BDNF) signaling as an important mediator of P4's protective actions. We have shown that P4 increases the expression of BDNF, an effect mediated by the classical P4 receptor (PR), and that the protective effects of P4 were abolished using inhibitors of Trk receptor signaling. In an effort to extend our understanding of the interrelationship between P4 and BDNF signaling, we determined whether P4 influenced BDNF release and examined the role of the classical PR and a putative membrane PR, progesterone receptor membrane component-1 (Pgrmc1), as mediators of this response. Given recent data from our laboratory that supported the role of ERK5 in BDNF release, we also tested whether P4-induced BDNF release was mediated by ERK5. In this study, we found that P4 and the membrane-impermeable P4 (P4-BSA) both induced BDNF release from cultured C6 glial cells and primary astrocytes. Both these cells lack the classical nuclear/intracellular PR but express high levels of membrane-associated PR, including Pgrmc1. Using RNA interference-mediated knockdown of Pgrmc1 expression, we determined that P4-induced BDNF release was dependent on the expression of Pgrmc1, although pharmacological inhibition of the PR failed to alter the effects of P4. Furthermore, the BDNF release elicited by P4 was mediated by ERK5, and not ERK1/2. Collectively, our data describe that P4 elicits an increase in BDNF release from glia via a Pgrmc1-induced ERK5 signaling mechanism and identify Pgrmc1 as a potential therapeutic target for future hormone-based drug development for the treatment of such degenerative diseases as Alzheimer's disease as well as other diseases wherein neurotrophin dysregulation is noted.

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The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer ◽

10.1016/j.bbcan.2016.07.004 ◽

2016 ◽

Vol 1866 (2) ◽

pp. 339-349 ◽

Cited By ~ 15

Author(s):

Michael A. Cahill ◽

Jalal A. Jazayeri ◽

Susan M. Catalano ◽

Shinya Toyokuni ◽

Zaklina Kovacevic ◽

...

Keyword(s):

Progesterone Receptor ◽

Cancer Biology ◽

Membrane Component ◽

Receptor Membrane

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Functional assessment of Progesterone Receptor Membrane Component 1 (PGRMC1) activity during bovine oocyte meiosis

Annals of Anatomy - Anatomischer Anzeiger ◽

10.1016/j.aanat.2016.04.012 ◽

2016 ◽

Vol 207 ◽

pp. 121

Author(s):

V. Lodde ◽

I. Tessaro ◽

F. Franciosi ◽

F. Raucci ◽

L. Terzaghi ◽

...

Keyword(s):

Progesterone Receptor ◽

Functional Assessment ◽

Bovine Oocyte ◽

Membrane Component ◽

Receptor Membrane ◽

Oocyte Meiosis

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Insight into progesterone receptor membrane component 1 action during bovine oocyte meiosis by means of siRNA-mediated gene silencing

Reproduction Abstracts ◽

10.1530/repabs.1.p044 ◽

2014 ◽

Author(s):

Valentina Lodde ◽

Irene Tessaro ◽

Franca Raucci ◽

Federica Franciosi ◽

Federica Marchese ◽

...

Keyword(s):

Progesterone Receptor ◽

Gene Silencing ◽

Bovine Oocyte ◽

Membrane Component ◽

Receptor Membrane ◽

Oocyte Meiosis ◽

Insight Into

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Progesterone receptor membrane component 1 expression and putative function in bovine oocyte maturation, fertilization, and early embryonic development

Reproduction ◽

10.1530/rep-10-0218 ◽

2010 ◽

Vol 140 (5) ◽

pp. 663-672 ◽

Cited By ~ 35

Author(s):

Alberto M Luciano ◽

Valentina Lodde ◽

Federica Franciosi ◽

Fabrizio Ceciliani ◽

John J Peluso

Keyword(s):

Progesterone Receptor ◽

Embryonic Development ◽

Oocyte Maturation ◽

Centromeric Region ◽

Confocal Imaging ◽

Membrane Component ◽

Aurora Kinase B ◽

Receptor Membrane ◽

Bovine Oocytes

Although the mRNA that encodes progesterone receptor membrane component 1 (PGRMC1) is present in mammalian oocytes, nothing is known about either PGRMC1's expression pattern or function in oocytes during maturation, fertilization, and subsequent embryonic development. As PGRMC1 associates with the mitotic spindle in somatic cells, we hypothesized that PGRMC1 is involved in oocyte maturation (meiosis). Western blot analysis confirmed the presence of PGRMC1 in bovine oocytes. This study also shows that PGRMC1 is present at the germinal vesicle (GV)- and MII-stage oocytes and is associated with male and female pronucleus formation of the zygote and is highly expressed in blastocysts. A more detailed examination of PGRMC1 localization using confocal imaging demonstrated that in GV-stage oocytes, PGRMC1 was concentrated throughout the GV but did not localize to the chromatin. With the resumption of meiosis in vitro, PGRMC1 concentrated in the centromeric region of metaphase I chromosomes, while in the anaphase I/telophase I stages the majority of PGRMC1 concentrated between the separating chromosomes. At the metaphase II stage, PGRMC1 re-associated with the centromeric region of the chromosomes. A colocalization study demonstrated that PGRMC1 associated with the phosphorylated form of aurora kinase B, which localizes to the centromeres at metaphase. Finally, PGRMC1 antibody injection significantly lowered the percentage of oocytes that matured and reached the metaphase II stage after 24 h of culture. The majority of the PGRMC1 antibody-injected oocytes arrested in the prometaphase I stage of meiosis. Furthermore, in most of the PGRMC1 antibody-injected oocytes, the chromosomes were disorganized and scattered. Taken together, these data demonstrate that PGRMC1 is expressed in bovine oocytes and its localization changes at specific stages of oocyte maturation. These observations suggest an important role for PGRMC1 in oocyte maturation, which may be specifically related to the mechanism by which chromosomes segregate.

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Progesterone increases blood glucose via hepatic progesterone receptor membrane component 1 under limited or impaired action of insulin

Scientific Reports ◽

10.1038/s41598-020-73330-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sang R. Lee ◽

Woo-Young Choi ◽

Jun H. Heo ◽

Jiyoung Huh ◽

Globinna Kim ◽

...

Keyword(s):

Blood Glucose ◽

Cyclic Amp ◽

Progesterone Receptor ◽

Insulin Action ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Membrane Component ◽

Receptor Membrane ◽

Hep3b Cells

Abstract Hepatic gluconeogenesis is the main pathway for blood glucose maintenance activated during fasting. Retardation of insulin action, such as in diabetes mellitus, activates gluconeogenesis during the fed state. While the role of progesterone (P4) in diabetes is controversial, the P4 receptor, progesterone receptor membrane component 1 (PGRMC1), is known to stimulate pancreatic insulin secretion. We investigated the role of P4, via hepatic PGRMC1, during gluconeogenesis. The PGRMC1 binding chemical, AG-205, induced PGRMC1 monomer (25 kDa) abundance, and increased PEPCK expression and glucose production in parallel with cyclic AMP (cAMP) induction in Hep3B cells. PGRMC1-mediated cyclic AMP was inhibited by an adenylate cyclase inhibitor (MDL-12,330A). PEPCK suppression in Pgrmc1 KO hepatocyte was not observed after treatment of MDL-12,330A. PGRMC1 knockdown or overexpression systems in Hep3B cells confirmed that PGRMC1 mediates PEPCK expression via phosphorylation of cAMP-response element binding protein (CREB). CREB phosphorylation and PEPCK expression in primary hepatocytes were greater than that in PGRMC1 knock-out hepatocytes. Progesterone increased PGRMC1 expression, which induced cAMP and PEPCK induction and glucose production. In vivo, P4 suppressed gluconeogenesis following plasma insulin induction under normal conditions in a mouse model. However, P4 increased blood glucose via gluconeogenesis in parallel with increases in PGRMC1 and PEPCK expression in mice in both insulin-deficient and insulin-resistant conditions. We conclude that P4 increases hepatic glucose production via PGRMC1, which may exacerbate hyperglycaemia in diabetes where insulin action is limited.

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