| First Author | Gurzov EN | Year | 2012 |
| Journal | Oncogene | Volume | 31 |
| Issue | 13 | Pages | 1723-32 |
| PubMed ID | 21841823 | Mgi Jnum | J:186146 |
| Mgi Id | MGI:5431076 | Doi | 10.1038/onc.2011.353 |
| Citation | Gurzov EN, et al. (2012) Pancreatic beta-cells activate a JunB/ATF3-dependent survival pathway during inflammation. Oncogene 31(13):1723-32 |
| abstractText | Destruction of insulin-producing pancreatic beta-cells by local autoimmune inflammation is a hallmark of type 1 diabetes. Histochemical analysis of pancreases from non-obese diabetic mice indicated activation of the transcription factor JunB/AP-1 (activator protein-1) after autoimmune infiltration of the islets. In vitro studies demonstrated that the cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma induce JunB expression as a protective mechanism against apoptosis in both human and rodent beta-cells. The gene network affected was studied by microarray analysis showing that JunB regulates nearly 20% of the cytokine-modified beta-cell genes, including the transcription factor ATF3. Direct transcriptional induction of ATF3 by JunB is a key event for beta-cell survival after TNF-alpha+IFN-gamma treatment. Moreover, pharmacological upregulation of JunB/ATF3 via increased cAMP protected rodent primary beta-cells and human islet cells against pro-inflammatory mediators. These results were confirmed in genetically modified islets derived from Ubi-JunB transgenic mice. Our findings identify ATF3 as a novel downstream target of JunB in the survival mechanism of beta-cells under inflammatory stress. |
