uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas
Show others and affiliations
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
Abstract [en]

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.
Keyword [en]
exome sequencing, insulinoma, YY1, cAMP, adenylyl cyclase
National Category
Endocrinology and Diabetes
URN: urn:nbn:se:uu:diva-251996DOI: 10.1073/pnas.1503696112ISI: 000351914500068PubMedID: 25787250OAI: oai:DiVA.org:uu-251996DiVA: diva2:810804
Available from: 2015-05-08 Created: 2015-04-28 Last updated: 2016-04-28

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Stålberg, PeterÅkerström, GöranWestin, GunnarHellman, PerBjörklund, Peyman
By organisation
Department of Surgical Sciences
In the same journal
Proceedings of the National Academy of Sciences of the United States of America
Endocrinology and Diabetes

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 194 hits
ReferencesLink to record
Permanent link

Direct link