jueves, 16 de octubre de 2014

Univadis - Diurnal suppression of ​EGFR signalling by glucocorticoids and implications for tumour progression and treatment

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Figure 2Activated ​GRs repress ​EGF-induced transcriptional programmes.
Activated GRs repress EGF-induced transcriptional programmes.
(a) RNA was isolated from MCF10A cells that were pretreated as indicated and hybridized to Affymetrix Exon Arrays. The heatmaps display RNA fold changes, which were clustered into four groups and ordered according to RNA’s peak time. (…

Diurnal suppression of ​EGFR signalling by glucocorticoids and implications for tumour progression and treatment

Nature Communications
Article number:


Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of ​EGFR, an RTK. The underlying mechanism entails suppression of ​EGFR’s positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain ​EGFR. Our studies in mice reveal that the regulation of ​EGFR’s feedback loops by glucocorticoids translates to circadian control of ​EGFR signalling: ​EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while ​EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing ​EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.

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