Prevention of Reg I-induced 尾-cell apoptosis by IL-6/dexamethasone through activation of HGF gene regulation
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- 作者：Kei Nakagawa ; Shin Takasawa ; Koji Nata ; Akiyo Yamauchi ; Asako Itaya-Hironaka ; Hiroyo Ota ; Kiyomi Yoshimoto ; Sumiyo Sakuramoto-Tsuchida ; Tomoko Miyaoka ; Maiko Takeda ; Michiaki Unno ; Hiroshi Okamoto
- 关键词：3AB ; 3-aminobenzamide ; ChIP ; Chromatin immunoprecipitation ; Dx ; dexamethasone ; FCS ; fetal calf serum ; GAPDH ; glyceraldehyde-3-phosphate dehydrogenase ; GATA ; transcription factor ; HGF ; hepatocyte growth factor ; HSF-2 ; heart shock factor 2 ; IL-6 ; interleukin-6 ; NA ; nicotinamide ; NOD mouse ; non-obese diabetic mouse ; Nrf-2 ; nuclear respiratory factor 2 ; PARP ; poly(ADP-ribose) polymerase ; Reg ; regenerating gene ; RT-PCR ; reverse transcription polymerase chain reaction ; STAT ; signal transducer and acti
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
- 出版年：December, 2013
- 年：2013
- 卷：1833
- 期：12
- 页码：2988-2995
- 全文大小：2823 K
文摘
Reg (regenerating gene) product, Reg protein, is induced in pancreatic 尾-cells and acts as autocrine/paracrine growth factor for regeneration via the cell surface Reg receptor. However, high concentrations of Reg I protein induced 尾-cell apoptosis. In the present study, we found that hepatocyte growth factor (HGF) attenuated the 尾-cell apoptosis induced by the high concentrations of Reg I protein and that the combined stimulation of interleukin-6 (IL-6) and dexamethasone (Dx) induced the accumulation of HGF mRNA as well as Reg I mRNA in 尾-cells. The accumulation of the HGF mRNA was caused by the activation of the HGF promoter. Deletion analysis revealed that the region of 鈭?#xA0;96 to 鈭?#xA0;92 of the HGF gene was responsible for the promoter activation by IL-6 + Dx. The promoters contain a consensus transcription factor binding sequence for signal transducer and activator of transcription (STAT). Site-directed mutations of STAT-binding motif in the region markedly attenuated the HGF promoter activity. Chromatin immunoprecipitation assay showed that STAT3 is located at the active HGF promoter in response to IL-6 + Dx stimulation. These results strongly suggest that the combined stimulation of IL-6 and glucocorticoids induces the activation of both Reg and HGF genes and that the anti-apoptotic effects of HGF against the Reg I-induced apoptosis may help 尾-cell regeneration by Reg I protein.