Functional Defects From Endocrine Disease-Associated Mutations in HLXB9 and Its Interacting Partner, NONO.
Functional Defects From Endocrine Disease-Associated Mutations in HLXB9 and Its Interacting Partner, NONO.
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DOI：
10.1210/en.2017-03155
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发表时间：
2018-02-01
期刊：
影响因子：
4.8
通讯作者：
Agarwal SK
中科院分区：
文献类型：
--
作者：
Kharade SS;Parekh VI;Agarwal SK
The insulin-secreting pancreatic neuroendocrine tumors, insulinomas, characterized by increased pancreatic islet β-cell proliferation, express the phosphorylated isoform of the β-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 β-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 β 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 β-cell excess (insulinomas) and in conditions of β-cell loss or dysfunction (diabetes). Our studies implicate therapeutic strategies for either reducing β-cell proliferation in insulinomas or alleviating normal β-cell deficiency in diabetes through the modulation of HLXB9 phosphorylation. Functional analysis showed that one of two HLXB9 mutations found in neonatal diabetes blocked phosphorylation and one of two NONO mutations found in endocrine tumors perturbed protein structure.
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DOI：
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