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J Cell Sci. 2019 Aug 22;132(16). pii: jcs230748. doi: 10.1242/jcs.230748.

Glucocorticoids delay RAF-induced senescence promoted by EGR1.

Author information

1
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
2
Service de Chimie Bio-organique et Marquage (SCBM), CEA, Université Paris-Saclay, 91191 Gif-sur-Yvette, France.
3
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, F-91057 Evry, France.
4
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France carl.mann@cea.fr jean-yves.thuret@cea.fr.

Abstract

Expression of hyperactive RAF kinases, such as the oncogenic B-RAF-V600E mutant, in normal human cells triggers a proliferative arrest that blocks tumor formation. We discovered that glucocorticoids delayed the entry into senescence induced by B-RAF-V600E in human fibroblasts, and allowed senescence bypass when the cells were regularly passaged, but that they did not allow proliferation of cells that were already senescent. Transcriptome and siRNA analyses revealed that the EGR1 gene is one target of glucocorticoid action. Transcription of the EGR1 gene is activated by the RAF-MEK-ERK MAPK pathway and acts as a sensor of hyper-mitogenic pathway activity. The EGR1 transcription factor regulates the expression of p15 and p21 (encoded by CDKN2B and CDKN1A, respectively) that are redundantly required for the proliferative arrest of BJ fibroblasts upon expression of B-RAF-V600E. Our results highlight the need to evaluate the action of glucocorticoid on cancer progression in melanoma, thyroid and colon carcinoma in which B-RAF-V600E is a frequent oncogene, and cancers in which evasion from senescence has been shown.

KEYWORDS:

B-RAF-V600E; CDKN1A; CDKN2B; EGR1; Glucocorticoid; Oncogene-induced senescence

PMID:
31371485
DOI:
10.1242/jcs.230748

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