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Ectopic expression of the beta-cell specific transcription factor Pdx1 inhibits glucagon gene transcription

Ritz-Laser, B.
Gauthier, B. R.
Estreicher, A.
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Published in Diabetologia. 2003, vol. 46, no. 6, p. 810-821
Collection Open Access - Licence nationale Springer
Abstract AIMS/HYPOTHESIS: The transcription factor Pdx1 is required for the development and differentiation of all pancreatic cells. Beta-cell specific inactivation of Pdx1 in developing or adult mice leads to an increase in glucagon-expressing cells, suggesting that absence of Pdx1could favour glucagon gene expression by a default mechanism. METHOD: We investigated the inhibitory role of Pdx1 on glucagon gene expression in vitro. The glucagonoma cell line InR1G9 was transduced with a Pdx1-encoding lentiviral vector and insulin and glucagon mRNA levels were analysed by northern blot and real-time PCR. To understand the mechanism by which Pdx1 inhibits glucagon gene expression, we studied its effect on glucagon promoter activity in non-islet cells using transient transfections and gel-shift analysis. RESULTS: In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%. In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. CONCLUSION/INTERPRETATION: Cell-specific expression of the glucagon gene can only occur when Pdx1 expression extinguishes from the early alpha cell precursor.
Keywords AnimalsBase SequenceBinding SitesCell LineCricetinaeGenetic VectorsGlucagon/ geneticsHomeodomain Proteins/genetics/metabolismHumansInsulin/geneticsIslets of Langerhans/physiologyMesocricetusMolecular Sequence DataOligodeoxyribonucleotidesOrgan SpecificityTrans-Activators/ genetics/metabolismTranscription, Genetic/ geneticsTransfection
PMID: 12783165
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RITZ-LASER, B. et al. Ectopic expression of the beta-cell specific transcription factor Pdx1 inhibits glucagon gene transcription. In: Diabetologia, 2003, vol. 46, n° 6, p. 810-821. doi: 10.1007/s00125-003-1115-7 https://archive-ouverte.unige.ch/unige:8998

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Deposited on : 2010-07-12

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