RGD Reference Report - Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma. - Rat Genome Database

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Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma.

Authors: Hamze, Z  Vercherat, C  Bernigaud-Lacheretz, A  Bazzi, W  Bonnavion, R  Lu, J  Calender, A  Pouponnot, C  Bertolino, P  Roche, C  Stein, R  Scoazec, JY  Zhang, CX  Cordier-Bussat, M 
Citation: Hamze Z, etal., Endocr Relat Cancer. 2013 Oct 24;20(6):833-48. doi: 10.1530/ERC-13-0164. Print 2013 Dec.
RGD ID: 9589069
Pubmed: PMID:24157940   (View Abstract at PubMed)
PMCID: PMC3841063   (View Article at PubMed Central)
DOI: DOI:10.1530/ERC-13-0164   (Journal Full-text)

The protein MENIN is the product of the multiple endocrine neoplasia type I (MEN1) gene. Altered MENIN expression is one of the few events that are clearly associated with foregut neuroendocrine tumours (NETs), classical oncogenes or tumour suppressors being not involved. One of the current challenges is to understand how alteration of MENIN expression contributes to the development of these tumours. We hypothesised that MENIN might regulate factors maintaining endocrine-differentiated functions. We chose the insulinoma model, a paradigmatic example of well-differentiated pancreatic NETs, to study whether MENIN interferes with the expression of v-MAF musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA), a master glucose-dependent transcription factor in differentiated beta-cells. Immunohistochemical analysis of a series of human insulinomas revealed a correlated decrease in both MENIN and MAFA. Decreased MAFA expression resulting from targeted Men1 ablation was also consistently observed in mouse insulinomas. In vitro analyses using insulinoma cell lines showed that MENIN regulated MAFA protein and mRNA levels, and bound to Mafa promoter sequences. MENIN knockdown concomitantly decreased mRNA expression of both Mafa and beta-cell differentiation markers (Ins1/2, Gck, Slc2a2 and Pdx1) and, in parallel, increased the proliferation rate of tumours as measured by bromodeoxyuridine incorporation. Interestingly, MAFA knockdown alone also increased proliferation rate but did not affect the expression of candidate proliferation genes regulated by MENIN. Finally, MENIN variants with missense mutations detected in patients with MEN1 lost the WT MENIN properties to regulate MAFA. Together, our findings unveil a previously unsuspected MENIN/MAFA connection regarding control of the beta-cell differentiation/proliferation balance, which could contribute to tumorigenesis.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Men1Ratpositive regulation of transcription by RNA polymerase II  IMP MafaRGD 
Men1Ratregulation of type B pancreatic cell proliferation  IMP negative regulationRGD 
Men1Rattype B pancreatic cell differentiation  IMP  RGD 

Molecular Function
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Men1Ratchromatin binding  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Men1  (menin 1)


Additional Information