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Modulation de la sénescence induite par les oncogènes par les glucocorticoïdes et rôle de EGR1

Abstract : Cellular senescence is a tumor suppressor mechanism. Indeed, it corresponds to an irreversible cell cycle arrest, in response for instance to the expression of an activated oncogene. In vivo, nevi, 80% of which express the B-RAF-V600E oncogene, are composed of cells that expressed an oncogene and became senescent, protecting against progression to melanoma. Nevertheless, B-RAF-V600E is found in 50% of malignant melanoma, which implies mechanisms of senescence escape. During my PhD, I studied the mechanisms of senescence induction by B-RAF-V600E, and a possible escape mechanism by glucocorticoids (GC). GC are often used in topical treatment of skin diseases for their anti-inflammatory properties, and are also used as immunosuppressant. We observed that they interfere with senescence induction in vitro. While studying the effects of GC, I identifiedone of their targets, transcription factor EGR1, and showed that GC repress EGR1 which positively controls the expression of cell cycle inhibitors CDKN2B and CDKN1A. EGR1 acts as a sensor of the level of MAPK/ERK pathway activation to induce a rapid cell-cycle arrest. I also showed that GC, but not the loss of EGR1, allow full escape to senescence induced by BRAF-V600E, implying the existence of other targets. My results demonstrate the role of EGR1 in senescence induction, and highlight the need to evaluate GC action on tumorigenesis linked to B-RAF-V600E, as well as in the higher prevalence of skin cancers in transplanted patients.
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Cyril Carvalho. Modulation de la sénescence induite par les oncogènes par les glucocorticoïdes et rôle de EGR1. Cancer. Université Paris-Saclay, 2018. Français. ⟨NNT : 2018SACLS183⟩. ⟨tel-01968059⟩

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