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Promoter-context as a determinant of glucocorticoid receptor-responsiveness to activation of p38 and JNK mitogen-activated protein (MAP) kinases

Zoltan Szatmary - Anton Kebis

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Rok, strany / Year, pages: 2012, 309-322

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Publikované / Published: 0000-00-00

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MAP kinases JNK and p38 play an important role in many immune and inflammatory processes, whereas glucocorticoids exert immunosuppressive and anti-inflammatory activities. We found previously that activation of p38 or JNK inhibits glucocorticoid receptor (GR)-mediated transcriptional activation of a mouse mammary tumor virus (MMTV) promoter-driven luciferase construct in HeLa cells. It appears that this effect is DNA regulatory element-specific, since p38 or JNK activation stimulates GR-dependent transcription from TAT3-ADH promoter-luciferase construct in the same cells. The apparent promoter-specificity of this action suggests that not all glucocorticoid-activated genes are negatively regulated by p38 or JNK. Using different MMTV/TAT3 chimeric reporters we demonstrate that the presence of other accessory binding sites of the MMTV construct contributes to the inhibitory effect of activated p38 or JNK on the MMTV-driven transcriptional activity; and diminishes, but does not reverse the stimulation observed using the TAT GREs from the TAT3-ADH promoter-luciferase construct. On the other hand, comparison of the effects of GRE sequences, either in isolation or in the context of the MMTV LTR accessory binding sites, demonstrates that the responsiveness of the GR depends on the GRE sequence; indicating that in addition to transcription factors bound nearby, interaction with the DNA itself modulates GR activity.

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