Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During Aging.
Adenomatous Polyposis Coli Protein
/ genetics
Aging
/ physiology
Animals
Cell Cycle Checkpoints
Cellular Senescence
/ physiology
Female
Humans
Interstitial Cells of Cajal
/ physiology
Klotho Proteins
/ genetics
Male
Mice
Mice, Transgenic
Middle Aged
Models, Animal
Stomach
/ cytology
Tumor Suppressor Protein p53
/ metabolism
Up-Regulation
Wnt Signaling Pathway
Young Adult
Compliance
Senescence
Stem Cell
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2021
2021
Historique:
received:
20
12
2019
revised:
29
07
2020
accepted:
30
07
2020
pubmed:
11
8
2020
medline:
21
12
2021
entrez:
11
8
2020
Statut:
ppublish
Résumé
Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates Wnt (wingless-type MMTV integration site) signaling. Here, we examined whether unopposed Wnt signaling could underlie aging-associated ICC loss by up-regulating transformation related protein TRP53 in ICC stem cells (ICC-SC). Mice aged 1-107 weeks, klotho mice, APC The klotho and aged mice showed similar ICC loss and impaired gastric compliance. ICC-SC decline preceded ICC depletion. Canonical Wnt signaling and TRP53 increased in gastric muscles of klotho and aged mice and middle-aged humans. Overstimulated canonical Wnt signaling increased DNA damage response and TRP53 and reduced ICC-SC self-renewal and gastric ICC. TRP53 induction persistently inhibited G Increased Wnt signaling causes age-related ICC loss by up-regulating TRP53, which induces persistent ICC-SC cell cycle arrest without up-regulating canonical senescence markers.
Sections du résumé
BACKGROUND & AIMS
Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates Wnt (wingless-type MMTV integration site) signaling. Here, we examined whether unopposed Wnt signaling could underlie aging-associated ICC loss by up-regulating transformation related protein TRP53 in ICC stem cells (ICC-SC).
METHODS
Mice aged 1-107 weeks, klotho mice, APC
RESULTS
The klotho and aged mice showed similar ICC loss and impaired gastric compliance. ICC-SC decline preceded ICC depletion. Canonical Wnt signaling and TRP53 increased in gastric muscles of klotho and aged mice and middle-aged humans. Overstimulated canonical Wnt signaling increased DNA damage response and TRP53 and reduced ICC-SC self-renewal and gastric ICC. TRP53 induction persistently inhibited G
CONCLUSIONS
Increased Wnt signaling causes age-related ICC loss by up-regulating TRP53, which induces persistent ICC-SC cell cycle arrest without up-regulating canonical senescence markers.
Identifiants
pubmed: 32771388
pii: S2352-345X(20)30117-X
doi: 10.1016/j.jcmgh.2020.07.011
pmc: PMC7672319
pii:
doi:
Substances chimiques
Adenomatous Polyposis Coli Protein
0
TP53 protein, human
0
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
adenomatous polyposis coli protein, mouse
0
Klotho Proteins
EC 3.2.1.31
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
117-145Subventions
Organisme : NIDDK NIH HHS
ID : P01 DK068055
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK058185
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NIDDK NIH HHS
ID : F31 DK089974
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK084567
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK121766
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR066036
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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