GSK-3? protein phosphorylates and stabilizes HLXB9 protein in insulinoma cells to form a targetable mechanism of controlling insulinoma cell proliferation.

ABSTRACT: Insulinomas (pancreatic islet ? 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 ? cell differentiation factor HLXB9 as a downstream target of menin (encoded by MEN1). Here we show that GSK-3? 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-3? are elevated in ? cells with menin knockdown, in MEN1-associated ? cell tumors (insulinomas), and also in human sporadic insulinomas. Pharmacologic inhibition of GSK-3? 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-3? and pHLXB9 forms a therapeutically targetable mechanism of insulinoma pathogenesis. Our results reveal that GSK-3? and pHLXB9 can serve as novel targets for insulinoma treatment and have implications for understanding the pathways associated with ? cell proliferation.

SUBMITTER: Desai SS 

PROVIDER: S-EPMC3937616 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature