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| [PMID]: | 29309627 |
| [Au] Autor: | Kharade SS; Parekh VI; Agarwal SK |
| [Ad] Endereço: | Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. |
| [Ti] Título: | Functional Defects From Endocrine Disease-Associated Mutations in HLXB9 and Its Interacting Partner, NONO. |
| [So] Source: | Endocrinology;159(2):1199-1212, 2018 02 01. | | [Is] ISSN: | 1945-7170 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | The insulin-secreting pancreatic neuroendocrine tumors, insulinomas, characterized by increased pancreatic islet ß-cell proliferation, express the phosphorylated isoform of the ß-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 ß-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 ß 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 ß-cell excess (insulinomas) and in conditions of ß-cell loss or dysfunction (diabetes). Our studies implicate therapeutic strategies for either reducing ß-cell proliferation in insulinomas or alleviating normal ß-cell deficiency in diabetes through the modulation of HLXB9 phosphorylation. |
| [Mh] Termos MeSH primário: |
Doenças do Sistema Endócrino/genética
Proteínas de Homeodomínio/genética
Proteínas de Homeodomínio/metabolismo
Proteínas Associadas à Matriz Nuclear/genética
Proteínas Associadas à Matriz Nuclear/metabolismo
Fatores de Transcrição de Octâmero/genética
Fatores de Transcrição de Octâmero/metabolismo
Proteínas de Ligação a RNA/genética
Proteínas de Ligação a RNA/metabolismo
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
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| [Mh] Termos MeSH secundário: |
Animais
Linhagem Celular Tumoral
Diabetes Mellitus/genética
Doenças do Sistema Endócrino/metabolismo
Mutação em Linhagem Germinativa
Seres Humanos
Recém-Nascido
Células Secretoras de Insulina/metabolismo
Células Secretoras de Insulina/patologia
Camundongos
Camundongos Transgênicos
Mutação
Ligação Proteica
Proteínas Proto-Oncogênicas/genética
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL |
[Nm] Nome de substância:
| 0 (Homeodomain Proteins); 0 (MNX1 protein, human); 0 (Men1 protein, mouse); 0 (NONO protein, human); 0 (Nuclear Matrix-Associated Proteins); 0 (Octamer Transcription Factors); 0 (Proto-Oncogene Proteins); 0 (RNA-Binding Proteins); 0 (Transcription Factors) |
| [Em] Mês de entrada: | 1802 |
| [Cu] Atualização por classe: | 180221 |
[Lr] Data última revisão:
| 180221 |
| [Sb] Subgrupo de revista: | AIM; IM |
| [Da] Data de entrada para processamento: | 180109 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1210/en.2017-03155 |
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