Migration des cellules tumorales : GEF et GAP montrent le chemin

International audienc

Regulation of Cdc42-mediated morphological effects: a novel function for p53

The tumour suppressor functions of p53 that are important for its activity depend on its role as a cell cycle arrest mediator and apoptosis inducer. Here we identify a novel function for p53 in regulating cell morphology and movement. We investigated the overall effect of p53 on morphological changes induced by RhoA, Rac1 and Cdc42 GTPases in mouse embryonic fibroblasts (MEFs). Interestingly, p53 exerted a selective effect on Cdc42-mediated cell functions. (i) Both overexpression of wild-type p53 and activation of endogenous p53 counteracted Cdc42-induced filopodia formation. Conversely, p53-deficient MEFs exhibited constitutive membrane filopodia. Mechanistic studies indicate that p53 prevents the initiating steps of filopodia formation downstream of Cdc42. (ii) Over expression of p53 modulates cell spreading of MEFs on fibronectin. (iii) During cell migration, the reorientation of the Golgi apparatus in the direction of movement is abolished by wild-type p53 expression, thus preventing cell polarity. Our data demonstrate a previously uncharacterized role for p53 in regulating Cdc42-dependent cell effects that control actin cytoskeletal dynamics and cell movement. This novel function may contribute to p53 anti-tumour activity

The South Pacific epidemic strain of Zika virus replicates efficiently in human epithelial A549 cells leading to IFN-β production and apoptosis induction

International audienc

Matrix-bound PAI-1, an extracellular modulator of cell functions: a novel member of the matricellular protein family

International audiencePAI-1 is a SERPIN found either soluble or bound to vitronectin in the matrix. In both cases, PAI-1 is a fast acting inhibitor for uPA. By that mean PAI-1 modulates all the processes influenced by uPA, such as development, wound healing, cancer cell migration, proteolysis, and in general, cell matrix interactions. In cell adhesion, PAI-1 plays directly a contradictory role: 1. interfering in Vitronectin/Integrin linking, i.e. in de adhesion, 2. as a member of the tripartite complex uPAR/uPA/PAI-1, promotes the linking of the cell membrane to ECM, i.e. intermediate adhesion. PAI-1 has also been evoked in another key cell function, migration and we previously showed that cancer cells of high invasivity were parallely increasing their migration when surrounded by a PAI-1 coat (1). As such, PAI-1 already appeared as an extracellular modulator of cell function. Here we present several additional experimental arguments for considering PAI-1 as a novel member of the matricellular protein family (2). 1. In an in vitro epithelial cell wound-healing model, where the main process is cell migration, a) we have shown that antibodies directed against PAI-1 were able to decrease the rate of closure; b) PAI-1 was expressed as an ECM-bound protein within 6 hours after wounding. 2. In epithelial colon cancer cells, a) matrix PAI-1 was able to reorganize the actin cytoskeleton (producing actin rings) and lead to the modification of the Rho/Rock pathway; b) matrix PAI-1 induces cell blebbing and amaeboid migration, a strong modification of cell behaviour. 3. In invasive mammary cancer cells, a) the expression of PAI-1 mRNAs was correlated with the presence of the transcription factor SNAIL, a major pro-migratory factor involved in embryogenesis, and cancer invasion; b) matrix PAI-1 induced an increase in steady state PAI-1 mRNA levels in cells where the expression of SNAIL has been switched off. These data strongly suggest matrix PAI-1 as an extracellular modulator of cell function, referring to the main family of matricellular protein