title: GSK-3β protein phosphorylates and stabilizes HLXB9 protein in insulinoma cells to form a targetable mechanism of controlling insulinoma cell proliferation.
abstract: Insulinomas (pancreatic islet β 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 β cell differentiation factor HLXB9 as a downstream target of menin (encoded by MEN1). Here we show that GSK-3β 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-3β are elevated in β cells with menin knockdown, in MEN1-associated β cell tumors (insulinomas), and also in human sporadic insulinomas. Pharmacologic inhibition of GSK-3β 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-3β and pHLXB9 forms a therapeutically targetable mechanism of insulinoma pathogenesis. Our results reveal that GSK-3β and pHLXB9 can serve as novel targets for insulinoma treatment and have implications for understanding the pathways associated with β cell proliferation.
authors.affiliation: From the Metabolic Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Shruti S
authors.initials: SS
authors.lastname: Desai
authors.forename: Sita D
authors.initials: SD
authors.lastname: Modali
authors.forename: Vaishali I
authors.initials: VI
authors.lastname: Parekh
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
authors.forename: Sunita K
authors.initials: SK
authors.lastname: Agarwal
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation / Q000235:genetics; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C105373:MEN1 protein, human; C490003:MNX1 protein, human; C484898:Men1 protein, mouse; C532041:Men1 protein, rat; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C084059:Hb9 protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: Differentiation; GSK-3β; HLXB9; Insulinoma; MEN1; Menin; Neuroendocrinology; Pancreatic Islets; Proliferation; Tumor