Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas

Cromer M. Kyle; Choi Murim; Nelson-Williams CarolFonseca Annabelle L.Kunstman John W.Korah Reju M.Overton John D.Mane ShrikantKenney BartonMalchoff Carl D.Stalberg PeterAkerstrom GoranWestin GunnarHellman PerCarling TobiasBjorklund PeymanLifton Richard P.

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Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas

机译：Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas

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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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2015年第13期|4062-4067|共6页
作者
Cromer M. Kyle; Choi Murim; Nelson-Williams CarolFonseca Annabelle L.Kunstman John W.Korah Reju M.Overton John D.Mane ShrikantKenney BartonMalchoff Carl D.Stalberg PeterAkerstrom GoranWestin GunnarHellman PerCarling TobiasBjorklund PeymanLifton Richard P.;
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作者单位

Uppsala Univ, Dept Surg Sci, S-75105 Uppsala, Sweden;

Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA;

Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USAYale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USAUniv Connecticut, Ctr Hlth, Div Endocrinol, Farmington, CT 06030 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
exome sequencing; insulinoma; YY1; cAMP; adenylyl cyclase;

Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas

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