| First Author | Desai SS | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 9 | Pages | 5386-98 |
| PubMed ID | 24425879 | Mgi Jnum | J:316232 |
| Mgi Id | MGI:6835037 | Doi | 10.1074/jbc.M113.533612 |
| Citation | Desai SS, et al. (2014) GSK-3beta protein phosphorylates and stabilizes HLXB9 protein in insulinoma cells to form a targetable mechanism of controlling insulinoma cell proliferation. J Biol Chem 289(9):5386-98 |
| abstractText | Insulinomas (pancreatic islet beta cell tumors) are the most common type of functioning pancreatic neuroendocrine tumors that occur sporadically or as a part of the MEN1 syndrome that is caused by germ line mutations in MEN1. Tissue-specific tumor predisposition from germ line mutations in ubiquitously expressed genes such as MEN1 could occur because of functional consequences on tissue-specific factors. We previously reported the proapoptotic beta cell differentiation factor HLXB9 as a downstream target of menin (encoded by MEN1). Here we show that GSK-3beta inactivates the proapoptotic activity of HLXB9 by phosphorylating HLXB9 at Ser-78/Ser-80 (pHLXB9). Although HLXB9 is found in the nucleus and cytoplasm, pHLXB9 is predominantly nuclear. Both pHLXB9 and active GSK-3beta are elevated in beta cells with menin knockdown, in MEN1-associated beta cell tumors (insulinomas), and also in human sporadic insulinomas. Pharmacologic inhibition of GSK-3beta blocked cell proliferation in three different rodent insulinoma cell lines by arresting the cells in G2/M phase and caused apoptosis. Taken together, these data suggest that the combination of GSK-3beta and pHLXB9 forms a therapeutically targetable mechanism of insulinoma pathogenesis. Our results reveal that GSK-3beta and pHLXB9 can serve as novel targets for insulinoma treatment and have implications for understanding the pathways associated with beta cell proliferation. |
