ArticleThe Journal of biological chemistry2014
GSK-3β protein phosphorylates and stabilizes HLXB9 protein in insulinoma cells to form a targetable mechanism of controlling insulinoma cell proliferation.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 16 citations in OpenAlex.
- MEN1-Related Neuroendocrine Tumors Show c-MET Overexpression.Journal of the Endocrine Society · 2025Article
- Unraveling the interplay: exploring signaling pathways in pancreatic cancer in the context of pancreatic embryogenesis.Frontiers in cell and developmental biology · 2024Review
- Pan-Cancer Analysis IdentifiesCells · 2022Article
- Novel insights into the role of aberrantly expressed MNX1 (HLXB9) in infant acute myeloid leukemia.Haematologica · 2019Article
- Expression, Clinical Significance, and Functional Prediction of MNX1 in Breast Cancer.Molecular therapy. Nucleic acids · 2018Article
- Motor neuron and pancreas homeobox 1/HLXB9 promotes sustained proliferation in bladder cancer by upregulating CCNE1/2.Journal of experimental & clinical cancer research : CR · 2018Article
- Frequency and consequence of the recurrentEndocrine-related cancer · 2018Article
- Functional Defects From Endocrine Disease-Associated Mutations in HLXB9 and Its Interacting Partner, NONO.Endocrinology · 2018Article
- Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets.Endocrine connections · 2018Review
- Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells.Molecular and cellular biology · 2017Article
- The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models.PloS one · 2017Article
- Inactivating the permanent neonatal diabetes gene Mnx1 switches insulin-producing β-cells to a δ-like fate and reveals a facultative proliferative capacity in aged β-cells.Development (Cambridge, England) · 2015Article
- Pro-oncogenic Roles of HLXB9 Protein in Insulinoma Cells through Interaction with Nono Protein and Down-regulation of the c-Met Inhibitor Cblb (Casitas B-lineage Lymphoma b).The Journal of biological chemistry · 2015Article
- Epigenetic regulation of the lncRNA MEG3 and its target c-MET in pancreatic neuroendocrine tumors.Molecular endocrinology (Baltimore, Md.) · 2015Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
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.
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