PMID- 38325289
OWN - NLM
STAT- MEDLINE
DCOM- 20240226
LR  - 20240409
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 165
IP  - 4
DP  - 2024 Feb 20
TI  - mTOR Regulates Mineralocorticoid Receptor Transcriptional Activity by 
      ULK1-Dependent and -Independent Mechanisms.
LID - 10.1210/endocr/bqae015 [doi]
LID - bqae015
AB  - The mineralocorticoid receptor (MR) is a transcription factor for genes mediating 
      diverse, cell-specific functions, including trophic effects as well as promoting 
      fluid/electrolyte homeostasis. It was reported that in intercalated cells, 
      phosphorylation of the MR at serine 843 (S843) by Unc-51-like kinase (ULK1) 
      inhibits MR activation and that phosphorylation of ULK1 by mechanistic target of 
      rapamycin (mTOR) inactivates ULK1, and thereby prevents MR inactivation. We 
      extended these findings with studies in M1 mouse cortical collecting duct cells 
      stably expressing the rat MR and a reporter gene. Pharmacological inhibition of 
      ULK1 dose-dependently increased ligand-induced MR transactivation, while ULK1 
      activation had no effect. Pharmacological inhibition of mTOR and CRISPR/gRNA gene 
      knockdown of rapamycin-sensitive adapter protein of mTOR (Raptor) or 
      rapamycin-insensitive companion of mTOR (Rictor) decreased phosphorylated ULK1 
      and ligand-induced activation of the MR reporter gene, as well as transcription 
      of endogenous MR-target genes. As predicted, ULK1 inhibition had no effect on 
      aldosterone-mediated transcription in M1 cells with the mutated MR-S843A (alanine 
      cannot be phosphorylated). In contrast, mTOR inhibition dose-dependently 
      decreased transcription in the MR-S843A cells, though not as completely as in 
      cells with the wild-type MR-S843. mTOR, Raptor, and Rictor coprecipitated with 
      the MR and addition of aldosterone increased their phosphorylated, active state. 
      These results suggest that mTOR significantly regulates MR activity in at least 2 
      ways: by suppressing MR inactivation by ULK1, and by a yet ill-defined mechanism 
      that involves direct association with MR. They also provide new insights into the 
      diverse functions of ULK1 and mTOR, 2 key enzymes that monitor the cell's energy 
      status.
CI  - Published by Oxford University Press on behalf of the Endocrine Society 2024.
FAU - Ali, Yusuf
AU  - Ali Y
AUID- ORCID: 0000-0003-0753-3590
AD  - Research Service, G. V. (Sonny) Montgomery VA Medical Center, Jackson, MS 39216, 
      USA.
AD  - Department of Pharmacology and Toxicology, University of Mississippi Medical 
      Center, Jackson, MS 39216, USA.
FAU - Gomez-Sanchez, Celso E
AU  - Gomez-Sanchez CE
AUID- ORCID: 0000-0002-9882-2082
AD  - Research Service, G. V. (Sonny) Montgomery VA Medical Center, Jackson, MS 39216, 
      USA.
AD  - Department of Pharmacology and Toxicology, University of Mississippi Medical 
      Center, Jackson, MS 39216, USA.
FAU - Plonczynski, Maria
AU  - Plonczynski M
AD  - Department of Pharmacology and Toxicology, University of Mississippi Medical 
      Center, Jackson, MS 39216, USA.
FAU - Naray-Fejes-Toth, Aniko
AU  - Naray-Fejes-Toth A
AD  - Department of Physiology, Dartmouth Medical School, Lebanon, NH 03755, USA.
FAU - Fejes-Toth, Geza
AU  - Fejes-Toth G
AD  - Department of Physiology, Dartmouth Medical School, Lebanon, NH 03755, USA.
FAU - Gomez-Sanchez, Elise P
AU  - Gomez-Sanchez EP
AUID- ORCID: 0000-0002-4432-4950
AD  - Department of Pharmacology and Toxicology, University of Mississippi Medical 
      Center, Jackson, MS 39216, USA.
LA  - eng
GR  - I01 BX004681/BX/BLRD VA/United States
GR  - R01 HL144847/HL/NHLBI NIH HHS/United States
GR  - U54 GM115428/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 4964P6T9RB (Aldosterone)
RN  - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog)
RN  - 0 (Ligands)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Receptors, Mineralocorticoid)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 0 (RNA, Guide, CRISPR-Cas Systems)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (ULK1 protein, rat)
RN  - EC 2.7.11.1 (Ulk1 protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Rats
MH  - *Aldosterone
MH  - Autophagy-Related Protein-1 Homolog/genetics/metabolism
MH  - Ligands
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Multiprotein Complexes/metabolism
MH  - Phosphorylation
MH  - Rapamycin-Insensitive Companion of mTOR Protein/metabolism
MH  - *Receptors, Mineralocorticoid/genetics/metabolism
MH  - Regulatory-Associated Protein of mTOR
MH  - RNA, Guide, CRISPR-Cas Systems
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Transcription Factors/metabolism
PMC - PMC10887451
OTO - NOTNLM
OT  - M1 cell
OT  - Raptor
OT  - Rictor
OT  - ULK1
OT  - aldosterone
OT  - mTOR
OT  - mineralocorticoid receptor
EDAT- 2024/02/08 00:41
MHDA- 2024/02/26 06:42
PMCR- 2024/02/07
CRDT- 2024/02/07 18:16
PHST- 2023/09/25 00:00 [received]
PHST- 2024/02/26 06:42 [medline]
PHST- 2024/02/08 00:41 [pubmed]
PHST- 2024/02/07 18:16 [entrez]
PHST- 2024/02/07 00:00 [pmc-release]
AID - 7603218 [pii]
AID - bqae015 [pii]
AID - 10.1210/endocr/bqae015 [doi]
PST - ppublish
SO  - Endocrinology. 2024 Feb 20;165(4):bqae015. doi: 10.1210/endocr/bqae015.