Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Human Molecular Genetics Année : 2011

Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase.

Résumé

FOXL2 is a transcription factor essential for ovarian function and maintenance, whose germline mutations are responsible for the Blepharophimosis syndrome (BPES), often associated with premature ovarian failure/ageing. Recent evidence has linked FOXL2 downregulation or somatic mutation (p.Cys134Trp) to cancer, though underlying molecular mechanisms remain unclear. Using a functional genomics approach, we find that FOXL2 modulates cell cycle regulators in a way which should lead to G1 arrest. Indeed, FOXL2 upregulation promotes cell accumulation in the G1 phase and protects cells from oxidative damage, notably by promoting oxidized DNA repair and by increasing the amounts of anti-oxidant agent Glutathione. In agreement with clinical observations, we find that FOXL2 mutated versions leading to BPES along with ovarian dysfunction mostly fail to transactivate cell-cycle and DNA repair targets, whereas mutations leading to isolated craniofacial defects (and normal ovarian function) activate them correctly. Interestingly, these assays revealed a mild promoter-specific hypomorphy of the tumor-associated mutation (p.Cys134Trp). Finally, the SIRT1 deacetylase suppresses FOXL2 activity on targets linked to cell cycle and DNA-repair in a dose-dependent manner. Accordingly, we find that SIRT1 inhibition by nicotinamide limits proliferation, notably by increasing endogenous FOXL2 amount/activity. The body of evidence presented here supports the idea that FOXL2 plays a key role in granulosa cell homeostasis, the failure of which is central to ovarian ageing and tumorigenesis. Since granulosa cell tumors respond poorly to conventional chemotherapy, our findings on the deacetylase inhibitor nicotinamide provide an interesting option for targeted therapy.

Dates et versions

hal-00566930 , version 1 (17-02-2011)

Identifiants

Citer

Bérénice A Benayoun, Adrien B Georges, David L'Hôte, Noora Andersson, Aurélie Dipietromaria, et al.. Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase.. Human Molecular Genetics, 2011, epub ahead of print. ⟨10.1093/hmg/ddr042⟩. ⟨hal-00566930⟩
110 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More