scholarly journals Regulation by Progestins, Corticosteroids, and RU486 of Transcriptional Activation of Elephant Shark and Human Progesterone Receptors: An Evolutionary Perspective

2021 ◽  
Author(s):  
Xiaozhi Lin ◽  
Wataru Takagi ◽  
Susumu Hyodo ◽  
Shigeho Ijiri ◽  
Yoshinao Katsu ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Progesterone Receptors ◽  
Evolutionary Perspective ◽  
Elephant Shark

scholarly journals Regulation by Progestins, Corticosteroids and RU486 of Activation of Elephant Shark and Human Progesterone Receptors: An Evolutionary Perspective

2021 ◽  
Author(s):  
Xiaozhi Lin ◽  
Wataru Takagi ◽  
Susumu Hyodo ◽  
Shigeho Ijiri ◽  
Yoshinao Katsu ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Progesterone Receptors ◽  
Cartilaginous Fish ◽  
Evolutionary Perspective ◽  
Elephant Shark ◽  
Hydroxy Progesterone

AbstractWe investigated progestin and corticosteroid activation of the progesterone receptor (PR) from elephant shark (Callorhinchus milii), a cartilaginous fish belonging to the oldest group of jawed vertebrates. Comparison with human PR experiments provides insights into the evolution of steroid activation of human PR. At 1 nM steroid, elephant shark PR is activated by progesterone, 17-hydroxy-progesterone, 20β-hydroxy-progesterone, 11-deoxycorticosterone (21-hydroxyprogesterone) and 11-deoxycortisol. At 1 nM steroid, human PR is activated only by progesterone and11-deoxycorticosterone indicating increased specificity for progestins and corticosteroids during the evolution of human PR. RU486, an important clinical antagonist of human PR, did not inhibit progesterone activation of elephant shark PR. Cys-528 in elephant shark PR corresponds to Gly-722 in human PR, which is essential for RU486 inhibition of human PR. Confirming the importance of this site on elephant shark PR, RU486 inhibited progesterone activation of the Cys528Gly mutant PR. There also was a decline in activation of elephant shark Cys528Gly PR by 11-deoxycortisol, 17-hydroxy-progesterone and 20β-hydroxy-progesterone and an increase in activation of human Gly722Cys PR by 11-deoxycortisol and decreased activation by corticosterone. One or more of these changes may have selected for the mutation corresponding to human glycine-722 PR that first evolved in platypus PR, a basal mammal.

scholarly journals Regulation by Progestins, Corticosteroids and RU486 of Activation of Elephant Shark and Human Progesterone Receptors: An Evolutionary Perspective

2021 ◽  
Author(s):  
Xiaozhi Lin ◽  
Wataru Takagi ◽  
Susumu Hyodo ◽  
Shigeho Ijiri ◽  
Yoshinao Katsu ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Progesterone Receptors ◽  
Cartilaginous Fish ◽  
Evolutionary Perspective ◽  
Elephant Shark ◽  
Hydroxy Progesterone

Abstract We investigated progestin and corticosteroid activation of the progesterone receptor (PR) from elephant shark (Callorhinchus milii), a cartilaginous fish belonging to the oldest group of jawed vertebrates. Comparison with human PR experiments provides insights into the evolution of steroid activation of human PR. At 1 nM steroid, elephant shark PR is activated by progesterone, 17-hydroxy-progesterone, 20b-hydroxy-progesterone, 11-deoxycorticosterone (21-hydroxyprogesterone) and 11-deoxycortisol. At 1 nM steroid, human PR is activated only by progesterone and11-deoxycorticosterone indicating increased specificity for progestins and corticosteroids during the evolution of human PR. RU486, an important clinical antagonist of human PR, did not inhibit progesterone activation of elephant shark PR. Cys-528 in elephant shark PR corresponds to Gly-722 in human PR, which is essential for RU486 inhibition of human PR. Confirming the importance of this site on elephant shark PR, RU486 inhibited progesterone activation of the Cys528Gly mutant PR. There also was a decline in activation of elephant shark Cys528Gly PR by 11-deoxycortisol, 17-hydroxy-progesterone and 20b-hydroxy-progesterone and an increase in activation of human Gly722Cys PR by 11-deoxycortisol and decreased activation by corticosterone. One or more of these changes may have selected for the mutation corresponding to human glycine-722 PR that first evolved in platypus PR, a basal mammal.

scholarly journals Transcriptional Activation of Elephant Shark Mineralocorticoid Receptor by Corticosteroids, Progesterone and Spironolactone

2018 ◽  
Author(s):  
Yoshinao Katsu ◽  
Satomi Kohno ◽  
Kaori Oka ◽  
Xiaozhi Lin ◽  
Sumika Otake ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Mineralocorticoid Receptor ◽  
Common Ancestor ◽  
Cartilaginous Fish ◽  
Full Length ◽  
Elephant Shark ◽  
Terrestrial Vertebrates ◽  
Epithelial Tissues ◽  
The Common ◽  
The Brain

AbstractWe report the analysis of activation of full-length mineralocorticoid receptor (MR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates by corticosteroids and progesterone. Based on their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fishes. Although progesterone activates ray-finned fish MRs, progesterone does not activate human, amphibian or alligator MRs, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Both elephant shark MR and human MR are expressed in the brain, heart, ovary, testis and other non-epithelial tissues, indicating that MR expression in diverse tissues evolved in the common ancestor of jawed vertebrates. Our data suggest that progesterone-activated MR may have unappreciated functions in elephant shark ovary and testis.

scholarly journals Transcriptional Activation of Elephant Shark Mineralocorticoid Receptor by Corticosteroids, Progesterone and Spironolactone

2019 ◽  
Author(s):  
Yoshinao Katsu ◽  
Satomi Kohno ◽  
Kaori Oka ◽  
Xiaozhi Lin ◽  
Sumika Otake ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Human Brain ◽  
Transcriptional Activation ◽  
Mineralocorticoid Receptor ◽  
Cartilaginous Fish ◽  
Full Length ◽  
Rna Sequence ◽  
Elephant Shark ◽  
Terrestrial Vertebrates ◽  
Cartilaginous Fishes

We report the analysis of activation by corticosteroids and progesterone of full-length mineralocorticoid receptor (MR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates.  Based on their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone are potential physiological mineralocorticoids.  However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fishes.  Because progesterone is a precursor for corticosteroids that activate elephant shark MR, we propose that progesterone was an ancestral ligand for elephant shark MR.  Although progesterone activates ray-finned fish MRs, progesterone does not activate human, amphibian or alligator MRs, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR.  Comparison of RNA-sequence analysis of elephant shark MR with that of human MR suggests that MR expression in the human brain, heart, ovary, testis and other non-epithelial tissues evolved in cartilaginous fishes.  Together, these data suggest that progesterone-activated MR may have unappreciated functions in elephant shark ovary and testis.

scholarly journals Transcriptional Activation of Elephant Shark Mineralocorticoid Receptor by Corticosteroids, Progesterone and Spironolactone

2019 ◽  
Author(s):  
Yoshinao Katsu ◽  
Satomi Kohno ◽  
Kaori Oka ◽  
Xiaozhi Lin ◽  
Sumika Otake ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Human Brain ◽  
Transcriptional Activation ◽  
Mineralocorticoid Receptor ◽  
Cartilaginous Fish ◽  
Full Length ◽  
Rna Sequence ◽  
Elephant Shark ◽  
Terrestrial Vertebrates ◽  
Cartilaginous Fishes

We report the analysis of activation by corticosteroids and progesterone of full-length mineralocorticoid receptor (MR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates. Based on their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fishes. Because progesterone is a precursor for corticosteroids that activate elephant shark MR, we propose that progesterone was an ancestral ligand for elephant shark MR. Although progesterone activates ray-finned fish MRs, progesterone does not activate human, amphibian or alligator MRs, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Comparison of RNA-sequence analysis of elephant shark MR with that of human MR suggests that MR expression in the human brain, heart, ovary, testis and other non-epithelial tissues evolved in cartilaginous fishes. Together, these data suggest that progesterone-activated MR may have unappreciated functions in elephant shark ovary and testis.

scholarly journals Transcriptional activation of elephant shark mineralocorticoid receptor by corticosteroids, progesterone, and spironolactone

2019 ◽  
Vol 12 (584) ◽  
pp. eaar2668 ◽  
Author(s):  
Yoshinao Katsu ◽  
Satomi Kohno ◽  
Kaori Oka ◽  
Xiaozhi Lin ◽  
Sumika Otake ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Mineralocorticoid Receptor ◽  
Common Ancestor ◽  
Cartilaginous Fish ◽  
Reproductive Physiology ◽  
Elephant Shark ◽  
Terrestrial Vertebrates ◽  
The Common ◽  
The Brain

The mineralocorticoid receptor (MR) is a nuclear receptor and part of a large and diverse family of transcription factors that also includes receptors for glucocorticoids, progesterone, androgens, and estrogens. The corticosteroid aldosterone is the physiological activator of the MR in humans and other terrestrial vertebrates; however, its activator is not known in cartilaginous fish, the oldest group of extant jawed vertebrates. Here, we analyzed the ability of corticosteroids and progesterone to activate the full-length MR from the elephant shark (Callorhinchus milii). On the basis of their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone, and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fish. Although progesterone activates MRs in ray-finned fish, progesterone does not activate MRs in humans, amphibians, or alligator, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Both elephant shark MR and human MR are expressed in the brain, heart, ovary, testis, and other nonepithelial tissues, suggesting that MR expression in diverse tissues evolved in the common ancestor of jawed vertebrates. Our data suggest that 19-norprogesterone– and progesterone-activated MR may have unappreciated functions in reproductive physiology.

Interactions of exogenous endocrine active substances with nuclear receptors

2003 ◽  
Vol 75 (11-12) ◽  
pp. 1797-1817 ◽  
Author(s):  
J. A. Katzenellenbogen ◽  
R. Muthyala
Keyword(s):  
Ligand Binding ◽  
Nuclear Receptors ◽  
Endocrine Disruption ◽  
Transcriptional Activation ◽  
Progesterone Receptors ◽  
Binding Pocket ◽  
Receptor Interaction ◽  
Hormone Production ◽  
Binding Domains ◽  
Equilibrium Dissociation

Nuclear receptors function as ligand-regulated transcription factors and modulate the expression of sets of genes in response to varying concentrations of ligands. The ligand modulators can be endogenous metabolites that function as hormones, or they can be exogenous substances, such as pharmaceutical agents or environmental substances of natural or man-made origin, which in some cases can cause endocrine disruption. Ligands modulate nuclear receptor activity by binding to their ligand-binding domains and stabilizing conformations that lead either to transcriptional activation or repression. The ligand-binding pocket is somewhat flexible, and binding affinities can be measured over a 10-million-fold range (i.e., with equilibrium dissociation constant values ranging from ca. 0.01 nM to 100 μM). Thus, it is not surprising that by binding a large variety of structures, some nuclear receptors can appear to be promiscuous; however, when affinity is considered, the binding patterns are more restricted. The spectrum of ligands that bind to the estrogen receptor has been most thoroughly investigated. Those from natural sources include natural products in food, such as soy isoflavones and whole grain lignans, as well as microbial products and components from wood. Aside from pharmaceuticals, man-made estrogen ligands can be found in industrial products, such as alkyl phenols from nonionic detergents, bisphenols from plastics, indicator dye impurities, polymer chemicals, and chlorinated aromatics and pesticides. Exogenous ligands are also known for the androgen and progesterone receptors. While it is possible that endocrine disruption can result from exogenous chemicals acting directly as ligands for the nuclear receptors, endocrine disruption needs to be considered in the broader context; thus, compounds also need to be assessed for their effects at other levels, such as on endogenous hormone production, transport, metabolism, and clearance, and at points in signal transduction cascades that are beyond the ligand-receptor interaction.

Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity

2019 ◽  
Vol 476 (24) ◽  
pp. 3705-3719 ◽  
Author(s):  
Avani Vyas ◽  
Umamaheswar Duvvuri ◽  
Kirill Kiselyov
Keyword(s):  
Oxidative Stress ◽  
Head And Neck ◽  
Transcriptional Activation ◽  
Platinum Resistance ◽  
Mrna Levels ◽  
Strong Positive Correlation ◽  
Platinum Compounds ◽  
Copper Chelation ◽  
Novel Approach ◽  
Cancer Models

Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.

Role of molecular chaperones in steroid receptor action

2004 ◽  
Vol 40 ◽  
pp. 41-58 ◽  
Author(s):  
William B Pratt ◽  
Mario D Galigniana ◽  
Yoshihiro Morishima ◽  
Patrick J M Murphy
Keyword(s):  
Transcriptional Activation ◽  
Protein Trafficking ◽  
Steroid Receptors ◽  
Transcriptional Regulatory ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Receptor Action ◽  
Binding Cleft ◽  
Hsp 90

Unliganded steroid receptors are assembled into heterocomplexes with heat-shock protein (hsp) 90 by a multiprotein chaperone machinery. In addition to binding the receptors at the chaperone site, hsp90 binds cofactors at other sites that are part of the assembly machinery, as well as immunophilins that connect the assembled receptor-hsp90 heterocomplexes to a protein trafficking pathway. The hsp90-/hsp70-based chaperone machinery interacts with the unliganded glucocorticoid receptor to open the steroid-binding cleft to access by a steroid, and the machinery interacts in very dynamic fashion with the liganded, transformed receptor to facilitate its translocation along microtubular highways to the nucleus. In the nucleus, the chaperone machinery interacts with the receptor in transcriptional regulatory complexes after hormone dissociation to release the receptor and terminate transcriptional activation. By forming heterocomplexes with hsp90, the chaperone machinery stabilizes the receptor to degradation by the ubiquitin-proteasome pathway of proteolysis.

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