Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas
2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 13, 4062-4067 p.Article in journal (Refereed) Published
Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca2+ channel); both are expressed at very low levels in normal beta-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca2+ signaling pathways involved in insulin secretion.
Place, publisher, year, edition, pages
2015. Vol. 112, no 13, 4062-4067 p.
exome sequencing, insulinoma, YY1, cAMP, adenylyl cyclase
Endocrinology and Diabetes
IdentifiersURN: urn:nbn:se:uu:diva-251996DOI: 10.1073/pnas.1503696112ISI: 000351914500068PubMedID: 25787250OAI: oai:DiVA.org:uu-251996DiVA: diva2:810804