Contrôle par les glucocorticoïdes et par l'insuline de gènes transcrits dans le foie
(1998)
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- The steroid-bound glucocorticoid receptor (GR) binds to genes and modulates the rate of initiation of their transcription. GR activity is regulated by protein kinase in response to extracellular signals and by specific interactions with transcription factors or co-activators. We have investigated how liver-enriched transcription factors and insulin modulate the glucocorticoids stimulation of genes in rat liver. <BR> We found that the stimulation of the gene coding for 6-phosphofructo-2-kinase (PFK-2) by glucocorticoids occurs via an intronic glucocorticoid response unit (GRU) that, contrary to the GRU of other genes, is in an open chromatin structure. Using a combination of transfection experiments and of in vitro and in vivo protein-DNA interaction studies, we found that the PFK-2 GRU contains binding sites for the GR and for the liver-enriched transcription factors HNF-3 and HFN-6. We showed that HNF-3 cooperates with the GR and that this cooperation occurs via GR-induced HNF-3 binding DNA. In contrast, HNF-6 antagonized glucocorticoid action upon binding to the PFK-2 GRU. We found that the NH2-terminal part of HNF-6 interacts with the DNA binding domain of GR, thereby leading to the inhibition of GR activity. We also observed this antiglucocorticoid effect of HNF-6 on the phosphoenolpyruvate carboxykinase gene promoter. <BR> Insulin regulates the transcription of a number of genes in liver via a phosphatidylinositol 3-kinase- or a mitogen-activated protein kinase-dependent pathway. We found that insulin inhibits the glucocorticoid stimulation of the PFK-2 gene via another pathway and through a novel mechanism. These studies showed that the insulin signalling cascade does not act via an insulin response element in DNA but that it targets the steroid binding domain of the GR, thereby leading to inhibition of GR activity. <BR> In conclusion, we have identified novel mechanisms for the antiglucocorticoid activity exerted by insulin and by the liver-enriched transcription factor HNF-6
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Pierreux, C. (1998). Contrôle par les glucocorticoïdes et par l’insuline de gènes transcrits dans le foie. https://hdl.handle.net/2078.5/111502