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• W2130711943 abstract "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 α (TNFα). As dynamic rearrangements of actin cytoskeleton control cell locomotion, this implicates that TNFα is a potent coordinator of cellular actin changes. We have investigated the role of TNFα in regulating the cortical actin-containing structures essential for cell locomotion called filopodia. Kinetic analysis of TNFα-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 TNFα 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, TNFα 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 TNFα-dependent filopodia inhibition. Our data delineate a novel inhibitory pathway in which TNFα 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 TNFα on its own initiates antagonistic signals that modulate events linked to cell migration." @default.
• W2130711943 created "2016-06-24" @default.
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• W2130711943 date "2004-12-15" @default.
• W2130711943 modified "2023-10-13" @default.
• W2130711943 title "TNFα induces sequential activation of Cdc42- and p38/p53-dependent pathways that antagonistically regulate filopodia formation" @default.
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• W2130711943 doi "https://doi.org/10.1242/jcs.01566" @default.
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