Etude de l'activité protectrice du FGF1 intracellulaire vis-à-vis de l'apoptose induite par p53

La protéine oncosuppressive p53 et les facteurs de croissance tel que le FGF1 ont un rôle fondamental à l'interface entre cycle cellulaire, apoptose et survie. L'étude des relations entre ces deux protéines dans des fibroblastes embryonnaires et des cellules de type neuronal nous a permis de montrer que la protéine FGF1 inhibe l activité pro-apoptotique de p53 par un mode d action intracrine. La protéine FGF1 empêche la stabilisation et l activation fonctionnelle de la protéine p53. Ainsi, l action protectrice de FGF1 peut s expliquer par sa capacité à inhiber l activité transactivatrice de p53 vis-à-vis de gènes tels que bax (fibroblastes) et puma (neurones) qui codent pour des protéines pro-apoptotiques de la famille BCL-2, initiatrices de la voie mitochondriale de l apoptoseThe p53 oncosuppresive protein and the growth factors, like FGF1, are essential to control the cell cycle and apoptosis. Study of the relationship between these two proteins, in embryo fibroblasts and sympathetic like neurons, had shown that FGF1 protein can inhibit the pro-apoptotic activity of p53 by an intracrine pathway. FGF1 factor inhibits p53 stability and its transcriptional activity, notably on bax (fibroblasts) and puma (neurons) genes. PUMA and NOXA are BH3-only pro-apoptotic proteins of the BCL-2 family that induce the mitochondrial pathway of apoptosis.VERSAILLES-BU Sciences et IUT (786462101) / SudocSudocFranceF

Pink is involved in Drosophila Bcl-2 protein family-dependent apoptosis

International audienc

Interconnexion between mitophagy and mitochondrial apoptosis

National audienc

Is PINK1 involved in Drosophila Bcl-2 family protein-dependent apoptosis?

National audienc

PINK1 and BNIP3 mitophagy inducers have an antagonistic effect on Rbf1-induced apoptosis in Drosophila

The structure and function of the mitochondrial network are finely regulated. Among the proteins involved in these regulations, mitochondrial dynamics actors have been reported to regulate the apoptotic process. We show here in the Drosophila model that the mitophagy inducers, PINK1 (PTENinduced putative kinase 1) and BNIP3 (Bcl-2 Interacting Protein 3), modulate mitochondrial apoptosis differently. If close links between the fission-inducing protein DRP1 and Bcl-2 family proteins, regulators of apoptosis, are demonstrated, the connection between mitophagy and apoptosis is still poorly understood. In Drosophila, we have shown that Rbf1, a homolog of the oncosuppressive protein pRb, induces cell death in proliferating larval tissues through a mechanism involving the interaction of Drp1 with Debcl, a pro-apoptotic protein of the Bcl-2 family. This interaction is necessary to induce mitochondrial fission, ROS production, and apoptosis. To better understand the interactions between the proteins involved in mitochondrial homeostasis and the apoptotic process, we focused on the role of two known players in mitophagy, the proteins PINK1 and BNIP3, during mitochondrial apoptosis induced by Rbf1 and Debcl in a proliferating Drosophila larval tissue. We show that Rbf1-or Debcl-induced apoptosis is accompanied by mitophagy. Interestingly, PINK1 and BNIP3 have distinct effects in regulating cell death. PINK1 promotes rbf1-or debcl-induced apoptosis, whereas BNIP3 protects against Rbf1-induced apoptosis but reduces Debclinduced tissue loss without inhibiting Debcl-induced cell death. Furthermore, our results indicate that BNIP3 is required to induce basal mitophagy while PINK1 is responsible for mitophagy induced by rbf1 overexpression. These results highlight the critical role of mitophagy regulators in controlling homeostasis and cell fate

FGF1 induces resistance to chemotherapy in ovarian granulosa tumor cells through regulation of p53 mitochondrial localization

International audienceOvarian cancer remains associated with a high mortality rate and relapse is too frequently seen after chemotherapeutic treatment of granulosa cell tumors (GCTs) or epithelial ovarian cancers (EOCs). It is thus of major importance to progress in the knowledge of the molecular mechanisms underlying chemoresistance of ovarian tumors. Overexpression of Fibroblast Growth Factor 1 (FGF1) is observed in various cancers, correlates with poor survival and could be responsible for resistance to platinum-based chemotherapy of serous ovarian cancers. How FGF1 promotes escape to chemotherapy remains unknown. In previous studies, we showed that FGF1 inhibits p53 transcriptional activities, leading to increased cell survival of neuronal or fibroblast cell lines. In this study, we show that FGF1 favors survival of COV434 cells upon treatment with etoposide and cisplatin, two common chemotherapeutic molecules used for ovarian cancer. Etoposide and cisplatin induced mitochondrial depolarization, cytochrome c release and caspase activation in COV434 cells. Overexpression of FGF1 counteracts these events and thus allows increased survival of ovarian cells. In this study, FGF1 had little effect on p53 stability and transcriptional activities. Etoposide induced p21 expression as expected, but p21 protein levels were even increased in the presence of FGF1. Using RNA interference, we showed that p21 exerts an anti-apoptotic activity in COV434 cells. However abrogating this activity was not sufficient to restore cell death of FGF1-overexpressing cells. We also show for the first time that p53 mitochondrial pathway is involved in the cell death of COV434 cells. Indeed, p53 accumulates at mitochondria upon etoposide treatment and inhibition of p53 mitochondrial localization using pifithrin-µ inhibits apoptosis of COV434 cells. FGF1 also decreases mitochondrial accumulation of p53 induced by etoposide. This constitutes a novel mechanism of action for FGF1 to promote cell survival in response to chemotherapy

Insights into the roles of the Sideroflexins / SLC56 family in iron homeostasis and iron-sulfur biogenesis

International audienceSideroflexins (SCL56) are highly conserved multi-spanning transmembrane proteins inserted in the inner mitochondrial membrane in eukaryotes. Few data are available on their molecular function but, since their first description, they were thought to be metabolite transporters maybe required for iron utilization inside the mitochondrion. Such as numerous mitochondrial transporters, sideroflexins remain poorly characterized. The prototypic member SFXN1 was recently identified as the previously unknown mitochondrial transporter of serine but pending questions on the molecular function of sideroflexins remain, especially their link with iron. Here, we review the current knowledge on sideroflexins, their presumed mitochondrial functions and the sparse - but growing - evidence linking sideroflexins to iron homeostasis and iron-sulfur proteins. Since an imbalance in iron homeostasis favors retinal degeneration, we also investigate the relationships between sideroflexins, iron and retinal degeneration. Research on Sideroflexins’ functions constitute an emerging research field of great interest and will certainly lead to main discoveries on mitochondrial physiopatholog

FGF1 nuclear translocation is required for both its neurotrophic activity and its p53-dependent apoptosis protection

No commentInternational audienceFibroblast growth factor 1 (FGF1) is a differentiation and survival factor for neuronal cells both in vitro and in vivo. FGF1 activities can be mediated not only by paracrine and autocrine pathways involving FGF receptors but also by an intracrine pathway, which is an underestimated mode of action. Indeed, FGF1 lacks a secretion signal peptide and contains a nuclear localization sequence (NLS), which is consistent with its usual intracellular and nuclear localization. To progress in the comprehension of the FGF1 intracrine pathway in neuronal cells, we examined the role of the nuclear translocation of FGF1 for its neurotrophic activity as well as for its protective activity against p53-dependent apoptosis. Thus, we have transfected PC12 cells with different FGF1 expression vectors encoding wild type or mutant (Δ NLS) FGF1. This deletion inhibited both FGF1 nuclear translocation and FGF1 neurotrophic activity (including differentiation and serum-free cell survival). We also show that endogenous FGF1 protection of PC12 cells against p53-dependent cell death requires FGF1 nuclear translocation. Strikingly, wild type FGF1 is found interacting with p53, in contrast to the mutant FGF1 deleted of its NLS, suggesting the presence of direct and/or indirect interactions between FGF1 and p53 pathways. Thus, we present evidences that FGF1 may act by a nuclear pathway to induce neuronal differentiation and to protect the cells from apoptosis whether cell death is induced by serum depletion or p53 activation