| First Author | Liu Z | Year | 2016 |
| Journal | Cell Death Differ | Volume | 23 |
| Issue | 9 | Pages | 1529-41 |
| PubMed ID | 27128598 | Mgi Jnum | J:258911 |
| Mgi Id | MGI:6140264 | Doi | 10.1038/cdd.2016.38 |
| Citation | Liu Z, et al. (2016) beta-Arrestin-2 modulates radiation-induced intestinal crypt progenitor/stem cell injury. Cell Death Differ 23(9):1529-41 |
| abstractText | 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 beta-arrestin-2 (betaarr2)-mediated ICPS cell apoptosis is crucial for IR-stimulated intestinal injury. betaArr2-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 betaarr2-deficient mice depended on prolonged nuclear factor-kappaB (NF-kappaB) activation via direct interaction of betaarr2 with IkappaBalpha and subsequent inhibition of p53-upregulated modulator of apoptosis (PUMA)-mediated mitochondrial dysfunction. Unexpectedly, betaarr2 deficiency had little effect on IR-induced intestinal vascular endothelial cell apoptosis in mice. Consistently, betaarr2 knockdown also provided significant radioresistance by manipulating NF-kappaB/PUMA signaling in Lgr5(+) cells in vitro. Collectively, these observations show that targeting the betaarr2/NF-kappaB/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. betaArrs have recently been found to be multifunctional adaptor of apoptosis. Here, we found that beta-arrestin-2 (betaarr2) deficiency was associated with decreased radiation-induced ICPS cell apoptosis, which prolonged survival in abdominally irradiated mice. Moreover, betaarr2 deficiency-mediated intestinal progenitor/stem cell radioprotection relied on protracted NF-kappaB 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. betaArr2 is a potential target for lessening radiation-induced ICPS cell apoptosis. |
