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Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse

Oncogene volume 31, pages 3647–3654 (2012)Cite this article

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Abstract

MafB, a member of the large Maf transcription factor family, is essential for the embryonic and terminal differentiation of pancreatic α- and β-cells. However, the role of MafB in the control of adult islet-cell proliferation remains unknown. Considering its oncogenic potential in several other tissues, we investigated the possible alteration of its expression in adult mouse β-cells under different conditions of proliferation. We found that MafB, in general silenced in these cells, was reexpressed in ∼30% of adaptive β-cells both in gestational female mice and in mice fed with a high-fat diet. Importantly, reactivated MafB expression was also observed in the early β-cell lesions and insulinomas that developed in β-cell specific Men1 mutant mice, appearing in >80% of β-cells in hyperplasic or dysplastic islets from the mutant mice >4 months of age. Moreover, MafB expression could be induced by glucose stimulation in INS-1 rat insulinoma cells. The induction was further reinforced following Men1 knockdown by siRNA. Furthermore, MafB overexpression in cultured βTC3 cells enhanced cell foci formation both in culture medium and on soft agar, accompanied with the increased expression of Cyclin B1 and D2. Conversely, MafB downregulation by siRNA transfection reduced BrdU incorporation in INS-1E cells. Taken together, our data reveal that Men1 inactivation leads to MafB reexpression in mouse β-cells in vivo, and provides evidence that deregulated ectopic MafB expression may have a hitherto unknown role in adult β-cell proliferation and Men1-related tumorigenesis.

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Acknowledgements

We are grateful to Denis Ressnikoff for expert assistance of confocal microscopy, Jean-Michel Vicat and Martin Donnadieu for the maintenance of the mouse colonies, Dr Fabienne Rajas for help in high fat diet experiments, Pr. Jacques Philippe for Arx antibody, Dr Pierre Maechler for providing INS-1E line to M Cordier-Bussat. This study was supported by the Association pour la Recherche contre le Cancer (ARC), France, the Ligue contre le Cancer du Rhône and de la Loire, the MIRA program of Region Rhône-Alpes, National Science Foundation of China (NSFC30900700, 81170719, 30800537), and Science and Technology Commission of Shanghai Municipality (10140902900). J Lu and Z Hamze were the recipients of PhD-fellowship from ARC. J Lu was also the recipient of Shanghai Pujiang Program (10PJ1408900) and Shanghai New Excellent Youth Program (XYQ2011009).

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Authors and Affiliations

  1. Inserm U1052, Lyon, France

    J Lu, Z Hamze, R Bonnavion, F Assade, S Fontanière, P Bertolino, M Cordier-Bussat & C X Zhang

  2. CNRS UMR5286, Lyon, France

    J Lu, Z Hamze, R Bonnavion, F Assade, S Fontanière, P Bertolino, M Cordier-Bussat & C X Zhang

  3. Université de Lyon, Lyon, France

    J Lu, Z Hamze, R Bonnavion, F Assade, S Fontanière, P Bertolino, M Cordier-Bussat & C X Zhang

  4. Institut Curie, CNRS UMR 3347, INSERM U1021, Orsay, France

    N Herath & C Pouponnot

  5. The E-Institute of Shanghai, Sino-French Life Science and Genomic Center, Ruijin Hospital, Shanghai, China

    J Lu & C X Zhang

  6. Shanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao-Tong University, Shanghai, China

    J Lu

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  1. J Lu
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Correspondence to C X Zhang.

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Lu, J., Hamze, Z., Bonnavion, R. et al. Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse. Oncogene 31, 3647–3654 (2012). https://doi.org/10.1038/onc.2011.538

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  • DOI: https://doi.org/10.1038/onc.2011.538

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