Comparison of Transcriptional Activation by Corticosteroids of Human MR (Ile-180) and Human MR Haplotype (Ile180Val) DOI Creative Commons
Yoshinao Katsu, Jiawen Zhang, Ying Ao

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 11, 2024

Abstract While the classical function of human mineralocorticoid receptor (MR) is to regulate sodium and potassium homeostasis through aldosterone activation kidney MR, MR also highly expressed in brain, where activated by cortisol response stress. Here, we report half-maximal (EC50) fold-activation cortisol, other corticosteroids rs5522, a haplotype containing valine at codon 180 instead isoleucine found wild-type (Ile-180). rs5522 (Val-180) has been studied for its actions brain involving coping with stress depression. We compared EC50 transfected into HEK293 cells either TAT3 promoter or MMTV promoter. Parallel studies investigated binding antagonists, spironolactone progesterone, rs5522. In promotor, had slightly higher similar level all corticosteroids. contrast, promoter, 5522 (lower affinity) (Ile-180), while EC50s corticosterone were lower was higher. Spironolactone progesterone antagonist activity (Ile-180) presence promoters cells.

Язык: Английский

The glucocorticoid receptor potentiates aldosterone-induced transcription by the mineralocorticoid receptor DOI Creative Commons
Thomas A. Johnson, Grégory Fettweis, Kaustubh Wagh

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(47)

Опубликована: Ноя. 14, 2024

The glucocorticoid and mineralocorticoid receptors (GR MR, respectively) have distinct, yet overlapping physiological pathophysiological functions. There are indications that both interact functionally physically, but the precise role of this interdependence is poorly understood. Here, we analyzed impact GR coexpression on MR genome-wide transcriptional responses chromatin binding upon activation by aldosterone glucocorticoids, ligands receptor. Transcriptional in absence result fewer regulated genes. In contrast, potentiates MR-mediated transcription, particularly response to aldosterone, cell lines more physiologically relevant model mouse colon organoids. altered a locus- ligand-specific way. Single-molecule tracking suggests presence contributes productive MR/aldosterone complexes chromatin. Together, our data indicate aldosterone-mediated activity, even glucocorticoids.

Язык: Английский

Процитировано

9
Mechanisms of ligand-mediated modulation of mineralocorticoid receptor signaling DOI
Peter J. Fuller, Jun Yang, Morag J. Young

и другие.

Molecular and Cellular Endocrinology, Год журнала: 2025, Номер unknown, С. 112504 - 112504

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

0
Impact of corticoid receptors on Alzheimer’s disease: a neuroendocrine perspective DOI
Falguni Goel,

Daksh Kumar,

Anushka Sharma

и другие.

Inflammopharmacology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 18, 2025

Язык: Английский

Процитировано

0
Mineralocorticoid Receptor Antagonist Use in Hypertension to Prevent Heart Failure DOI
Bertram Pitt, Anand Vaidya

JACC Heart Failure, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

0
Transcription factors form a ternary complex with NIPBL/MAU2 to localize cohesin at enhancers DOI Creative Commons
Grégory Fettweis, Kaustubh Wagh, Diana A. Stavreva

и другие.

Nucleic Acids Research, Год журнала: 2025, Номер 53(9)

Опубликована: Май 10, 2025

Abstract While the cohesin complex is a key player in genome architecture, how it localizes to specific chromatin sites not understood. Recently, we and others have proposed that direct interactions with transcription factors lead localization of cohesin-loader (NIPBL/MAU2) within enhancers. Here, identify two clusters LxxLL motifs NIPBL sequence regulate dynamics, interactome, NIPBL-dependent transcriptional programs. One these interacts MAU2 necessary for maintenance NIPBL–MAU2 heterodimer. The second cluster binds specifically ligand-binding domains steroid receptors. For glucocorticoid receptor (GR), examine detail its interaction surfaces MAU2. Using AlphaFold2 molecular docking algorithms, uncover GR–NIPBL–MAU2 ternary describe importance GR-dependent gene regulation. Finally, show multiple interact NIPBL–MAU2, likely using interfaces other than those characterized GR.

Язык: Английский

Процитировано

0
Bile acids target an exposed cavity in the glucocorticoid receptor modulating receptor self-assembly, chromatin binding and transcriptional activity DOI Creative Commons
Alba Jiménez‐Panizo, Thomas A. Johnson, Kaustubh Wagh

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Май 16, 2025

The glucocorticoid receptor (GR) is an essential transcription factor that controls metabolism and homeostasis. Glucocorticoids (GCs) activate the GR upon occupying internal ligand-binding pocket (LBP) of its domain (GR-LBD), which has been focus most previous structure-function studies. Synthetic GCs such as dexamethasone are widely used to treat inflammatory diseases, but their chronic use results in major side effects, whose molecular underpinnings remain unresolved. Here we present a thorough analysis topography GR-LBD ability bind small-molecule compounds, especially cholesterol derivatives. We show one important class steroids, bile acids, previously unidentified highly conserved, surface-exposed cavities on GR-LBD. acids affect turnover self-assembly living cells, modulating transcriptional activity. These findings reveal unrecognized mechanism regulation, with implications for design novel mechanisms action. Bile modulate activity binding exposed allosteric thereby influencing regulation cells.

Язык: Английский

Процитировано

0
The multimerization pathway of the glucocorticoid receptor DOI Creative Commons
Andrea Alegre‐Martí, Alba Jiménez‐Panizo,

Agustina L. Lafuente

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 12, 2024

Abstract The glucocorticoid receptor (GR) is a leading drug target due to its anti-inflammatory and immunosuppressive roles. functional oligomeric conformation of full-length GR (FL-GR), which key for biological activity, remains disputed. Here we present new crystal structure agonist-bound ligand-binding domain (GR-LBD) comprising eight copies non-canonical dimer. relevance this dimer multimerization in living cells has been verified by studying single-and double-point mutants FL-GR fluorescence microscopy (Number & Brightness) transcriptomic analysis. Self-association GR-LBD basic two mutually exclusive assemblies reveals clues activity cells. We propose model the multidomain based on our data suggest detailed oligomerization pathway. This reconciles all currently available structural information provides more comprehensive understanding rare resistance disorder (Chrousos syndrome).

Язык: Английский

Процитировано

2
Transcription factors form a ternary complex with NIPBL/MAU2 to localize cohesin at enhancers DOI Creative Commons
Grégory Fettweis, Kaustubh Wagh, Diana A. Stavreva

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

ABSTRACT While the cohesin complex is a key player in genome architecture, how it localizes to specific chromatin sites not understood. Recently, we and others have proposed that direct interactions with transcription factors lead localization of cohesin-loader (NIPBL/MAU2) within enhancers. Here, identify two clusters LxxLL motifs NIPBL sequence regulate dynamics, interactome, NIPBL-dependent transcriptional programs. One these interacts MAU2 necessary for maintenance NIPBL-MAU2 heterodimer. The second cluster binds specifically ligand-binding domains steroid receptors. For glucocorticoid receptor (GR), examine detail its interaction surfaces MAU2. Using AlphaFold2 molecular docking algorithms, uncover GR-NIPBL-MAU2 ternary describe importance GR-dependent gene regulation. Finally, show multiple interact NIPBL-MAU2, likely using interfaces other than those characterized GR.

Язык: Английский

Процитировано

0
Comparison of Transcriptional Activation by Corticosteroids of Human MR (Ile-180) and Human MR Haplotype (Ile180Val) DOI Creative Commons
Yoshinao Katsu, Jiawen Zhang, Ying Ao

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Abstract While the classical function of human mineralocorticoid receptor (MR) is to regulate sodium and potassium homeostasis through aldosterone activation kidney MR, MR also highly expressed in brain, where activated by cortisol response stress. Here, we report half-maximal (EC50) fold-activation cortisol, other corticosteroids rs5522, a haplotype containing valine at codon 180 instead isoleucine found wild-type (Ile-180). rs5522 (Val-180) has been studied for its actions brain involving coping with stress depression. We compared EC50 transfected into HEK293 cells either TAT3 promoter or MMTV promoter. Parallel studies investigated binding antagonists, spironolactone progesterone, rs5522. In promotor, had slightly higher similar level all corticosteroids. contrast, promoter, 5522 (lower affinity) (Ile-180), while EC50s corticosterone were lower was higher. Spironolactone progesterone antagonist activity (Ile-180) presence promoters cells.

Язык: Английский

Процитировано

0
Comparison of Transcriptional Activation by Corticosteroids of Human MR (Ile-180) and Human MR Haplotype (Ile180Val) DOI Creative Commons
Yoshinao Katsu, Jiawen Zhang, Ying Ao

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 11, 2024

Abstract While the classical function of human mineralocorticoid receptor (MR) is to regulate sodium and potassium homeostasis through aldosterone activation kidney MR, MR also highly expressed in brain, where activated by cortisol response stress. Here, we report half-maximal (EC50) fold-activation cortisol, other corticosteroids rs5522, a haplotype containing valine at codon 180 instead isoleucine found wild-type (Ile-180). rs5522 (Val-180) has been studied for its actions brain involving coping with stress depression. We compared EC50 transfected into HEK293 cells either TAT3 promoter or MMTV promoter. Parallel studies investigated binding antagonists, spironolactone progesterone, rs5522. In promotor, had slightly higher similar level all corticosteroids. contrast, promoter, 5522 (lower affinity) (Ile-180), while EC50s corticosterone were lower was higher. Spironolactone progesterone antagonist activity (Ile-180) presence promoters cells.

Язык: Английский

Процитировано

0