Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During AgingSummary

Autor: Huihuang Yan, Khashayarsha Khazaie, Gianrico Farrugia, Sabriya A. Syed, Michelle Wehling-Henricks, Makoto Kuro-o, Simon J. Gibbons, Sergiy M. Kvasha, David T. Asuzu, Rea A. Nagy, Eduardo N. Chini, Mahendra Pal Singh, Yujiro Hayashi, David R. Linden, James G. Tidball, Gabriella B. Gajdos, Michael R. Bardsley, Jair Machado Espindola Netto, Siva Arumugam Saravanaperumal, Todd A. Kellogg, Tamas Ordog, Yoshitaka Toyomasu
Jazyk: angličtina
Rok vydání: 2021
Předmět:
PE
R-phycoerythrin
Male
0301 basic medicine
CL.CASP3
cleaved caspase 3
Aging
Cell cycle checkpoint
BrdU
5-bromo-2′-deoxyuridine
DMSO
dimethyl sulfoxide
Mice
0302 clinical medicine
APC
allophycocyanin
ERK
extracellular signal-regulated kinase
GSEA
gene set enrichment analysis
GEO
Gene Expression Omnibus
NES
normalized enrichment score
TRP53
transformation related protein 53
Wnt Signaling Pathway
Klotho
ANOVA
analysis of variance
Cellular Senescence
Original Research
SA-β-gal
senescence-associated beta-galactosidase
KIT
v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
Stomach
EdU
5-ethynyl-2′-deoxyuridine
Gastroenterology
Wnt signaling pathway
MTS
methyltetrazolium salt
ICC
interstitial cells of Cajal
Middle Aged
CDKN1A
cyclin-dependent kinase inhibitor 1a
Up-Regulation
Cell biology
CTNNB1
catenin beta 1
GAPDH
glyceraldehyde-3-phosphate dehydrogenase
Models
Animal
symbols
Female
030211 gastroenterology & hepatology
ANO1
anoctamin-1
RPKM
reads per kilobase of transcript per million mapped reads
Stem cell
Compliance
Senescence
SESN
sestrin
tsTAg
tsA58-mutant SV40 large T antigen
Adenomatous Polyposis Coli Protein
FDR Q
false discovery rate Q value
Mice
Transgenic
KLF4
Kruppel-like factor 4
Biology
DDR
DNA damage response
PI
propidium iodide
Young Adult
03 medical and health sciences
symbols.namesake
Cyclin D1
RT-qPCR
real-time quantitative reverse-transcription polymerase chain reaction
Stem Cell
MEK
mitogen-activated protein kinase kinase
Animals
Humans
Kinase activity
lcsh:RC799-869
Klotho Proteins
CCND1
cyclin D1
Hepatology
WB
Western immunoblotting
RNA-seq
RNA sequencing
Cell Cycle Checkpoints
Interstitial Cells of Cajal
CDKN1B
cyclin-dependent kinase inhibitor 2B
WT
wild-type
Interstitial cell of Cajal
030104 developmental biology
siRNA
small interfering RNA
ETV1
ets variant 1
ICC-SC
interstitial cells of Cajal stem cells
lcsh:Diseases of the digestive system. Gastroenterology
Tumor Suppressor Protein p53
MYC
myelocytomatosis oncogene
DAPI
4′
6-diamidino-2-phenylindole
Zdroj: Cellular and Molecular Gastroenterology and Hepatology, Vol 11, Iss 1, Pp 117-145 (2021)
Cellular and Molecular Gastroenterology and Hepatology
Popis: 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, APCΔ468 mice with overactive Wnt signaling, mouse ICC-SC, and human gastric smooth muscles were studied by RNA sequencing, reverse transcription–polymerase chain reaction, immunoblots, immunofluorescence, histochemistry, flow cytometry, and methyltetrazolium, ethynyl/bromodeoxyuridine incorporation, and ex-vivo gastric compliance assays. Cells were manipulated pharmacologically and by gene overexpression and RNA interference. 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 G1/S and G2/M cell cycle phase transitions without activating apoptosis, autophagy, cellular quiescence, or canonical markers/mediators of senescence. G1/S block reflected increased cyclin-dependent kinase inhibitor 1B and reduced cyclin D1 from reduced extracellular signal-regulated kinase activity. 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.
Graphical abstract
Databáze: OpenAIRE
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