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

Abstract

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 Ca(2+) channel); both are expressed at very low levels in normal β-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 Ca(2+) signaling pathways involved in insulin secretion.

• Authors: M Kyle Cromer, Murim Choi, Carol Nelson-Williams, Annabelle L Fonseca, John W Kunstman, Reju M Korah, John D Overton, Shrikant Mane, Barton Kenney, Carl D Malchoff, Peter Stalberg, Göran Akerström, Gunnar Westin, Per Hellman, Tobias Carling, Peyman Björklund, Richard P Lifton
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 13 Pg. 4062-7 (Mar 31 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25787250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• CACNA2D2 protein, human
• Calcium Channels
• Insulin
• YY1 Transcription Factor
• YY1 protein, human
• Cyclic AMP
• Adenylyl Cyclases
• adenylyl cyclase 1
• Calcium

Topics

• Adenylyl Cyclases (metabolism)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Base Sequence
• Binding Sites
• Blood Glucose (metabolism)
• Calcium (metabolism)
• Calcium Channels (metabolism)
• Cohort Studies
• Cyclic AMP (metabolism)
• Female
• Gene Expression Regulation
• Humans
• Insulin (metabolism)
• Insulin-Secreting Cells (cytology)
• Insulinoma (genetics, metabolism)
• Male
• Middle Aged
• Molecular Sequence Data
• Mutation, Missense
• Pancreatic Neoplasms (genetics, metabolism)
• Protein Binding
• YY1 Transcription Factor (genetics, metabolism)