β-Arrestin2 encourages inflammation-induced epithelial apoptosis through ER stress/PUMA in colitis

Zeng, Lizhi; Jin, Tao; Liu, H L; Tan, Song; Yang, Yidong; Peng, Xiaojie; Liu, Z H; Jiang, Jie; Wu, Bin

doi:10.1038/mi.2014.104

Cited by 33 publications

(33 citation statements)

References 41 publications

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“…This indicated that β-arrestin2 promoted 5-FU-induced apoptosis in colon cancer cells. In a previous study by Zeng et al (29) it has been proved that β-arrestin2 promotes inflammation-induced epithelial apoptosis through ER stress/PUMA in colitis. Liu et al (17) demonstrated that β-arrestin2 deficiency was associated with radiation-induced intestinal crypt progenitor cell apoptosis through protracted NF-κB activation and suppression of PUMA.…”

Section: Discussionmentioning

confidence: 95%

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β‑arrestin2 promotes 5‑FU‑induced apoptosis via the NF‑κB pathway in colorectal cancer

Ren

Wang

et al. 2018

Oncol Rep

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It has been demonstrated that β‑arrestin2 is involved in the initiation and development of many types of cancers. However, its role in colorectal cancer (CRC) remains poorly understood. The present study investigated the role of β‑arrestin2 in CRC using CRC patient tissues as well as the LoVo and HCT116 CRC cell lines. Briefly, significantly higher expression of β‑arrestin2 was observed in CRC tissues compared with normal colon tissues. In addition, the downregulation of β‑arrestin2 reduced 5‑FU‑induced apoptosis in the LoVo cells, while the overexpression of β‑arrestin2 increased the apoptosis of HCT116 cells in vitro. Furthermore, the downregulation of β‑arrestin2 reduced the expression of the pro‑apoptotic proteins cleaved‑caspase‑3 and Bax, and increased the expression of the anti‑apoptotic protein Bcl‑2 after 5‑FU treatment. In addition, the expression of p‑p65 was increased after the β‑arrestin2 downregulation and was decreased after the β‑arrestin2 overexpression. However, β‑arrestin2 downregulation had no effect on the proliferation, migration and invasion capacity of the LoVo cells. In conclusion, these results indicated that β‑arrestin2 promoted 5‑FU‑induced CRC cell apoptosis via the NF‑κB pathway and may be used as a prognosis marker for CRC.

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Section: Discussionmentioning

confidence: 95%

“…Accumulating evidence has uncovered the role of β-arrestin2 in apoptosis (23,24) and the dual effect of β-arrestin2 in apoptosis (24)(25)(26)(27). Under different conditions, β-arrestin2 can be pro-apoptotic or anti-apoptotic (28)(29)(30). In the present study, 5-FU, as a core drug for CRC, was selected as a drug-interfering factor.…”

Section: Discussionmentioning

confidence: 96%

β‑arrestin2 promotes 5‑FU‑induced apoptosis via the NF‑κB pathway in colorectal cancer

Ren

Wang

et al. 2018

Oncol Rep

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“…β-arrs are involved in several types of diseases, including Parkinson’s disease, multiple sclerosis, cardiovascular conditions, and colitis by serving as a scaffold protein in various signaling pathways, including ERK1/2, Wnt/β-catenin and c-Src 15–17 . Previously, we discovered that β-arr2 contributed to the development of experimental colitis and mucosal repair in the process of UC 18, 19 . In addition to their role in receptor downregulation, β-arrs also act as scaffold proteins to accelerate signal transduction in the EP4 pathway.…”

Section: Introductionmentioning

confidence: 99%

COX-1/PGE2/EP4 alleviates mucosal injury by upregulating β-arr1-mediated Akt signaling in colitis

Peng

Tan

et al. 2017

Sci Rep

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COX-1/PGE2 is an important protective mediator in ulcerative colitis (UC). β-arrestin1 (β-arr1), which acts as a scaffold protein, is involved in PGE2-mediated signaling pathways. However, the interaction between PGE2 and β-arr1 in maintaining mucosal barrier integrity remains unexplored. In this study, we demonstrated that COX-1 and PGE2 were significantly decreased, and EP4 mRNA was downregulated in both UC patients and mice during the injury phase. PGE2 treatment was found to alleviate mucosal injury and induce EP4 expression during dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) mice. Following DSS-induced injury, β-arr1 deficient mice showed increased signs of colitis compared to β-arr1 WT mice, and the expression of PI3K and p-Akt were remarkably downregulated in β-arr1 deficient mice. In parallel, HCT116 cells transfected with β-arr1 siRNA were examined in the presence or absence of PGE2 in vitro. PGE2 treatment in the β-arr1 WT/KO DSS model and β-arr1 siRNA transfection of HCT116 cells confirmed that PGE2 upregulated β-arr1 in vivo and in vitro. Collectively, our results indicate that COX-1/PGE2/EP4 upregulates the β-arr1 mediated Akt signaling pathway to provide mucosal protection in colitis. Thus, these findings provide support for the future development and clinical application of COX-1/PGE2 in UC.

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“…These authors found β-arr2 expression to be a susceptibility factor in colitis (28). They demonstrated in cell culture studies that, β-arr2 binds eIF2α and induces ER stress thereby affecting epithelial apoptosis through p53-upregulated modulator of apoptosis (PUMA).…”

Section: Discussionmentioning

confidence: 99%

Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation

Sharma

Malik

Steury

et al. 2015

Inflammatory Bowel Diseases

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β-arrestin2 (β-arr2) identified as a scaffolding protein in GPCR desensitization, is a negative regulator of inflammation in polymicrobial sepsis. In this study we wanted to investigate the role of β-arr2 in intestinal inflammation, a site of persistent microbial stimulation. In the absence of β-arr2, mice exhibited greater extent of mucosal inflammation determined by cellular infiltration and expression of inflammatory mediators even under homeostatic conditions. Further, β-arr2 deficient mice were more susceptible to DSS induced colitis as demonstrated by greater body weight loss, higher disease activity index and shortened colon as compared to wild type (WT) mice. We also show that T cells from β-arr2 KO mice exhibit altered activation status under both basal and colitic conditions, implicating their involvement in disease induction. Further assessment of the role of β-arr2 in intrinsic T cell differentiation confirmed its importance in T cell polarization. Utilizing the T cell transfer model of colitis we demonstrate that T-cell specific-β-arr2 is important in limiting colitic inflammation; however it plays a paradoxical role in concurrent systemic wasting disease. Together, our study highlights a critical negative regulatory role of β-arr2 in intestinal inflammation and demonstrates a distinct role of T-cell-specific β-arr2 in systemic wasting disease.

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β-Arrestin2 encourages inflammation-induced epithelial apoptosis through ER stress/PUMA in colitis

Cited by 33 publications

References 41 publications

β‑arrestin2 promotes 5‑FU‑induced apoptosis via the NF‑κB pathway in colorectal cancer

β‑arrestin2 promotes 5‑FU‑induced apoptosis via the NF‑κB pathway in colorectal cancer

COX-1/PGE2/EP4 alleviates mucosal injury by upregulating β-arr1-mediated Akt signaling in colitis

Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation

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