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Increased susceptibility to dextran sulfate sodium-induced colitis in the endoplasmic reticulum stress transducer OASIS deficient mice.

ABSTRACT: OASIS is a basic leucine zipper (bZIP) transmembrane transcription factor that is activated in response to endoplasmic reticulum (ER) stress. Previously, we showed that OASIS regulates final maturation of goblet cells in the large intestine. In the present study, to elucidate the roles of OASIS under pathophysiological conditions, we examined the stress response and inflammatory responses in Oasis deficient (Oasis?/?) mice exposed to dextran sulfate sodium (DSS) to induce colitis. A significant loss of body weight and an increase of mortality were observed in Oasis?/? mice with DSS-induced colitis compared with those in WT mice. The mucosa of the large intestine in Oasis?/? mice exhibited severe damage involving inflammatory cell infiltration. The expression levels of ER stress and apoptosis markers in intestinal epithelial cells were upregulated in Oasis?/? mice. These abnormalities were improved by treatment with tauroursodeoxycholic acid, a chemical chaperone that facilitates protein folding. Taken together, our findings demonstrate that OASIS plays important roles in protection of the large intestinal mucosa in DSS-induced colitis through attenuation of ER stress and inflammation.

SUBMITTER: Hino K

PROVIDER: S-EPMC3912207 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Increased susceptibility to dextran sulfate sodium-induced colitis in the endoplasmic reticulum stress transducer OASIS deficient mice.

Hino Kenta K Saito Atsushi A Asada Rie R Kanemoto Soshi S Imaizumi Kazunori K

PloS one 20140203 2

OASIS is a basic leucine zipper (bZIP) transmembrane transcription factor that is activated in response to endoplasmic reticulum (ER) stress. Previously, we showed that OASIS regulates final maturation of goblet cells in the large intestine. In the present study, to elucidate the roles of OASIS under pathophysiological conditions, we examined the stress response and inflammatory responses in Oasis deficient (Oasis⁻/⁻) mice exposed to dextran sulfate sodium (DSS) to induce colitis. A significant ...[more]

PMID: 24498426

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Project description:BackgroundVascular endothelial growth factor-A (VEGFA) is the main mediator of angiogenesis. Angiogenesis plays important roles not only in many physiological processes, but also in the pathophysiology of many diseases. VEGFA is one of the therapeutic targets of treatment for ocular diseases with neovascularization. Therefore, elucidation of the regulatory mechanisms for VEGFA expression is important for the development of pharmaceutical drugs. Recent studies have demonstrated that the unfolded protein response is involved in the transcriptional regulation of VEGFA. However, the precise regulation of VEGFA in the human retina is not fully understood.Principal findingsWhen human retinal pigment epithelial cells, ARPE-19, were exposed to endoplasmic reticulum stressors, VEGFA mRNA was significantly upregulated. The unfolded protein response-related transcription factors XBP1, ATF4, ATF6, and OASIS were expressed in ARPE-19 cells. To determine which transcription factors preferentially contribute to the induction of VEGFA expression after endoplasmic reticulum stress, we carried out reporter assays using an approximately 6-kbp 5'-upstream region of the human VEGFA gene. Among these transcription factors, OASIS acted most effectively on the VEGFA promoter in ARPE-19 cells. Based on data obtained for certain deleted and mutated reporter constructs, we determined that OASIS promoted VEGFA expression by acting on a cyclic AMP-responsive element-like site located at around -500 bp relative to the VEGFA transcription start site. Furthermore, we confirmed that OASIS directly bound to the promoter region containing this site by chromatin immunoprecipitation assays.Conclusions and significanceWe have demonstrated a novel regulatory mechanism for VEGFA transcription by OASIS in human retinal pigment epithelial cells. Chemical compounds that regulate the binding of OASIS to the promoter region of the VEGFA gene may have potential as therapeutic agents for ocular diseases with neovascularization.

Dataset Information

Increased susceptibility to dextran sulfate sodium-induced colitis in the endoplasmic reticulum stress transducer OASIS deficient mice.

Publications

Increased susceptibility to dextran sulfate sodium-induced colitis in the endoplasmic reticulum stress transducer OASIS deficient mice.

Similar Datasets

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