Unknown

Dataset Information

0

?-Arrestin-2 modulates radiation-induced intestinal crypt progenitor/stem cell injury.


ABSTRACT: Intestinal crypt progenitor/stem (ICPS) cell apoptosis and vascular endothelial cell apoptosis are responsible for the initiation and development of ionizing radiation (IR)-evoked gastrointestinal syndrome. The signaling mechanisms underlying IR-induced ICPS cell apoptosis remain largely unclear. Our findings provide evidence that ?-arrestin-2 (?arr2)-mediated ICPS cell apoptosis is crucial for IR-stimulated intestinal injury. ?Arr2-deficient mice exhibited decreased ICPS cell and intestinal Lgr5(+) (leucine-rich repeat-containing G-protein-coupled receptor 5-positive) stem cell apoptosis, promoted crypt proliferation and reproduction, and protracted survival following lethal doses of radiation. Radioprotection in the ICPS cells isolated from ?arr2-deficient mice depended on prolonged nuclear factor-?B (NF-?B) activation via direct interaction of ?arr2 with I?B? and subsequent inhibition of p53-upregulated modulator of apoptosis (PUMA)-mediated mitochondrial dysfunction. Unexpectedly, ?arr2 deficiency had little effect on IR-induced intestinal vascular endothelial cell apoptosis in mice. Consistently, ?arr2 knockdown also provided significant radioresistance by manipulating NF-?B/PUMA signaling in Lgr5(+) cells in vitro. Collectively, these observations show that targeting the ?arr2/NF-?B/PUMA novel pathway is a potential radiomitigator for limiting the damaging effect of radiotherapy on the gastrointestinal system. Significance statement: acute injury to the intestinal mucosa is a major dose-limiting complication of abdominal radiotherapy. The issue of whether the critical factor for the initiation of radiation-induced intestinal injury is intestinal stem cell apoptosis or endothelial cell apoptosis remains unresolved. ?Arrs have recently been found to be multifunctional adaptor of apoptosis. Here, we found that ?-arrestin-2 (?arr2) deficiency was associated with decreased radiation-induced ICPS cell apoptosis, which prolonged survival in abdominally irradiated mice. Moreover, ?arr2 deficiency-mediated intestinal progenitor/stem cell radioprotection relied on protracted NF-?B activation and subsequent suppression of PUMA induction. Our results suggest that ICPS cell apoptosis is the factor involved in the initiation and development of radiation-induced gastrointestinal syndrome. ?Arr2 is a potential target for lessening radiation-induced ICPS cell apoptosis.

SUBMITTER: Liu Z 

PROVIDER: S-EPMC5072429 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications

β-Arrestin-2 modulates radiation-induced intestinal crypt progenitor/stem cell injury.

Liu Z Z   Tian H H   Jiang J J   Yang Y Y   Tan S S   Lin X X   Liu H H   Wu B B  

Cell death and differentiation 20160429 9


Intestinal crypt progenitor/stem (ICPS) cell apoptosis and vascular endothelial cell apoptosis are responsible for the initiation and development of ionizing radiation (IR)-evoked gastrointestinal syndrome. The signaling mechanisms underlying IR-induced ICPS cell apoptosis remain largely unclear. Our findings provide evidence that β-arrestin-2 (βarr2)-mediated ICPS cell apoptosis is crucial for IR-stimulated intestinal injury. βArr2-deficient mice exhibited decreased ICPS cell and intestinal Lgr  ...[more]

Similar Datasets

| S-EPMC8466099 | biostudies-literature
| S-EPMC4536042 | biostudies-literature
| S-EPMC4893006 | biostudies-literature
| S-EPMC5542208 | biostudies-literature
| S-EPMC5797353 | biostudies-literature
| S-EPMC4846698 | biostudies-other
| S-EPMC4911500 | biostudies-literature
| S-EPMC4904973 | biostudies-other
| S-EPMC3252352 | biostudies-literature
| S-EPMC4071372 | biostudies-literature