Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment
| Autor: | Morris E. Feldman, Lee Roth, Hadas Cohen-Dvashi, Moshit Lindzen, Fernando Schmitt, Rossella Solmi, Michal Sharon-Sevilla, Amit Zeisel, Stefan Wiemann, Yehoshua Enuka, Gabriele D'Uva, Mattia Lauriola, Nir Ben-Chetrit, Yosef Yarden, Nava Nevo, Eytan Domany, Silvia Carvalho, Alon Chen, Kirti Sharma, Merav Kedmi |
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| Přispěvatelé: | Lauriola M, Enuka Y, Zeisel A, D'Uva G, Roth L, Sharon-Sevilla M, Lindzen M, Sharma K, Nevo N, Feldman M, Carvalho S, Cohen-Dvashi H, Kedmi M, Ben-Chetrit N, Chen A, Solmi R, Wiemann S, Schmitt F, Domany E, Yarden Y. |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
MAP Kinase Signaling System EGFR Circadian clock General Physics and Astronomy Biology Ligands Article General Biochemistry Genetics and Molecular Biology Receptor tyrosine kinase Mice Receptors Glucocorticoid Cell Movement Cell Line Tumor Neoplasms Oscillometry Internal medicine Negative feedback medicine Animals Humans Receptor Glucocorticoids Mice Knockout Multidisciplinary Kinase General Chemistry Circadian Rhythm ErbB Receptors Mice Inbred C57BL Treatment Outcome Endocrinology Nuclear receptor Disease Progression Cancer research biology.protein Female Signal transduction Signal Transduction Hormone |
| Zdroj: | Nature Communications |
| Popis: | 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. Glucocorticoids are released in a diurnal pattern. Here, the authors show that EGF receptor (EGFR) signalling is negatively regulated by glucocorticoids, and that EGFR inhibitor has stronger antitumour effects when administered during the resting phase, when glucocorticoids are low, offering potential optimization of cancer therapy regimens. |
| Databáze: | OpenAIRE |
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