TNFalpha induces sequential activation of Cdc42- and p38/p53-dependent pathways that antagonistically regulate filopodia formation.
Cell migration is an essential function in various physiological processes, including tissue repair and tumour invasion. Repair of tissue damage requires the recruitment of fibroblasts to sites of tissue injury, which is mediated in part by the cytokine tumour necrosis factor alpha (TNFalpha). As dynamic rearrangements of actin cytoskeleton control cell locomotion, this implicates that TNFalpha is a potent coordinator of cellular actin changes. We have investigated the role of TNFalpha in regulating the cortical actin-containing structures essential for cell locomotion called filopodia. Kinetic analysis of TNFalpha-treated mouse embryonic fibroblasts (MEFs) revealed a dual effect on filopodia formation: a rapid and transient induction mediated by Cdc42 GTPase that is then counteracted by a subsequent sustained inhibition requiring activation of the mitogen-activated protein kinase p38 but not Cdc42 activity. This inhibition also involves the tumour suppressor p53, given that it is activated in response to TNFalpha following the same time course as the decrease of filopodia formation. This functional activation of p53, measured by transcription induction of its target p21WAF1(p21), is also associated with p38 kinase-dependent phosphorylation of p53 at serine 18. Furthermore, TNFalpha did not inhibit filopodia formation in MEFs treated with the transcription inhibitor actinomycin D, in p53-deficient MEFs, or MEFs expressing p53 mutants H273 or H175, which supports a role for the transcriptional activity of p53 in mediating TNFalpha-dependent filopodia inhibition. Our data delineate a novel inhibitory pathway in which TNFalpha prevents filopodia formation and cell migration through the activation of the mitogen-activated protein kinase (MAPK) p38, which in turn activates p53. This shows that TNFalpha on its own initiates antagonistic signals that modulate events linked to cell migration.
Gadea
Gilles
G
Centre de Recherche en Biochimie Macromoléculaire, CNRS FRE 2593, IFR 24, 1919 route de Mende, 34293 Montpellier CEDEX 5, France.
Roger
Lauréline
L
Anguille
Christelle
C
de Toledo
Marion
M
Gire
Véronique
V
Roux
Pierre
P
D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D011554:Pseudopodia / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein