Foxa2, a novel protein partner of the tumour suppressor menin, is deregulated in mouse and human MEN1 glucagonomas.

Abstract

Foxa2, known as one of the pioneer factors, plays a crucial role in islet development and endocrine functions. Its expression and biological functions are regulated by various factors, including, in particular, insulin and glucagon. However, its expression and biological role in adult pancreatic α-cells remain elusive. In the current study, we showed that Foxa2 was overexpressed in islets from α-cell-specific Men1 mutant mice, at both the transcriptional level and the protein level. More importantly, immunostaining analyses showed its prominent nuclear accumulation, specifically in α-cells, at a very early stage after Men1 disruption. Similar nuclear FOXA2 expression was also detected in a substantial proportion (12/19) of human multiple endocrine neoplasia type 1 (MEN1) glucagonomas. Interestingly, our data revealed an interaction between Foxa2 and menin encoded by the Men1 gene. Furthermore, using several approaches, we demonstrated the relevance of this interaction in the regulation of two tested Foxa2 target genes, including the autoregulation of the Foxa2 promoter by Foxa2 itself. The current study establishes menin, a novel protein partner of Foxa2, as a regulator of Foxa2, the biological functions of which extend beyond the pancreatic endocrine cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Authors: Rémy Bonnavion, Romain Teinturier, Samuele Gherardi, Emmanuelle Leteurtre, Run Yu, Martine Cordier-Bussat, Rui Du, François Pattou, Marie-Christine Vantyghem, Philippe Bertolino, Jieli Lu, Chang Xian Zhang
• Journal: The Journal of pathology (J Pathol) Vol. 242 Issue 1 Pg. 90-101 (05 2017) ISSN: 1096-9896 [Electronic] England
• PMID: 28188614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• FOXA2 protein, human
• Foxa2 protein, mouse
• MEN1 protein, human
• Men1 protein, mouse
• Neoplasm Proteins
• Proto-Oncogene Proteins
• Hepatocyte Nuclear Factor 3-beta

Topics

• Animals
• Gene Expression Regulation, Neoplastic
• Glucagonoma (genetics, metabolism)
• Hepatocyte Nuclear Factor 3-beta (biosynthesis, genetics)
• Humans
• Mice, Transgenic
• Multiple Endocrine Neoplasia Type 1 (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Pancreatic Neoplasms (genetics, metabolism)
• Promoter Regions, Genetic (genetics)
• Proto-Oncogene Proteins (genetics, metabolism)
• Transfection
• Tumor Cells, Cultured