| First Author | Kharade SS | Year | 2018 |
| Journal | Endocrinology | Volume | 159 |
| Issue | 2 | Pages | 1199-1212 |
| PubMed ID | 29309627 | Mgi Jnum | J:257424 |
| Mgi Id | MGI:6115098 | Doi | 10.1210/en.2017-03155 |
| Citation | Kharade SS, et al. (2018) Functional Defects From Endocrine Disease-Associated Mutations in HLXB9 and Its Interacting Partner, NONO. Endocrinology 159(2):1199-1212 |
| abstractText | The insulin-secreting pancreatic neuroendocrine tumors, insulinomas, characterized by increased pancreatic islet beta-cell proliferation, express the phosphorylated isoform of the beta-cell differentiation factor HLXB9 that interacts with NONO/p54NRB, a survival factor. Interestingly, two different homozygous germline mutations in HLXB9, p.F248L and p.F272L, were reported in neonatal diabetes, a condition with functional beta-cell deficiency. Also, two somatic heterozygous NONO mutations were found in endocrine-related tumors, p.H146R (parathyroid) and p.R293H (small intestine neuroendocrine tumor). However, the biological consequence of the mutations, and the role of HLXB9-NONO interaction in normal or abnormal beta cells, is not known. Expression, localization, and functional analysis of the clinically relevant HLXB9 and NONO mutants showed that HLXB9/p.F248L mutant localized in the nucleus but lacked phosphorylation, and NONO/p.R293H mutant was structurally impaired. The HLXB9 and NONO mutants retained the ability to interact, and overexpression of wild-type or mutant HXLB9 in MIN6 cells suppressed cell proliferation. To further understand the biological consequence of the HLXB9-NONO interaction, we mapped the NONO-interacting region in HLXB9. An 80-amino acid conserved region of HLXB9 could compete with full-length HLXB9 to interact with NONO; however, in functional assays, nuclear expression of this HLXB9-conserved region in MIN6 cells did not interfere with cell proliferation. Overall, our results highlight the importance of HLXB9 in conditions of beta-cell excess (insulinomas) and in conditions of beta-cell loss or dysfunction (diabetes). Our studies implicate therapeutic strategies for either reducing beta-cell proliferation in insulinomas or alleviating normal beta-cell deficiency in diabetes through the modulation of HLXB9 phosphorylation. |
