期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：13
页码：4062-4067
DOI：10.1073/pnas.1503696112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe identical recurrent somatic heterozygous missense mutation in the DNA-binding domain of transcription factor YY1 is found in a third of insulin-secreting pancreatic tumors. This mutation alters sites involved in DNA contact and changes the DNA sequence motif that is bound, resulting in significant alteration of gene expression. Among genes showing markedly increased expression are two, an adenylyl cyclase (ADCY1) and a Ca2+ channel (CACNA2D2), that are involved in cAMP and Ca2+ signaling, processes known to play a role in insulin secretion. Expression of these genes in a pancreatic {beta}-cell line causes increased insulin release. These findings provide evidence for neomorphic effects of this mutation, and demonstrate a role for altered transcription factor specificity in neoplasia. 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 YY1T372R mutations. Genes showing large increases in expression in YY1T372R 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 YY1T372R mutations are neomorphic, resulting in constitutive activation of cAMP and Ca2+ signaling pathways involved in insulin secretion.
