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Disruption of basal JNK activity differentially affects key fibroblast functions important for wound healing.: Basal JNK activity regulates fibroblast functions

Abstract : We used both a gene knockout approach and pharmacologic modulation to study the implication of the JNK pathway in regulating fibroblast motility, capacity to contract mechanically unloaded collagen gels, and type I collagen gene expression in vitro. These parameters, which are important for tissue repair, are positively regulated by transforming growth factor (TGF)-beta, a cytokine viewed as playing a master role during wound healing. We demonstrate that basal JNK activity is critical for fibroblast motility because (a) mouse embryo jnk-/- fibroblasts exhibit significantly lower ability to close mechanically induced cell layer wounds than their wild-type (wt) counterparts, and (b) wound closure by human dermal fibroblasts is dramatically impaired by the specific JNK inhibitor SP600125. junAA fibroblasts, in which amino acids Ser63 and Ser73 of c-Jun are replaced by two Ala residues so that c-Jun cannot be phosphorylated by JNK, also exhibited impaired motility, suggesting that c-Jun phosphorylation by JNK is critical for fibroblast migration. In sharp contrast to their lesser motility on plastic, jnk-/- and junAA fibroblasts contracted free-floating, mechanically unloaded, collagen lattices markedly faster than wt fibroblasts. Furthermore, basal mRNA steady-state levels for types I and III collagen genes were similar in jnk-/- and wt fibroblasts. Likewise, overexpression of a dominant-negative mutant form of MKK4 in dermal fibroblasts did not affect collagen expression. We also demonstrate that basal JNK activity does not affect either TGF-beta-induced collagen gene expression or lattice contraction, whereas on the other hand, the blockage of motility initiated by JNK inhibition cannot be overcome by TGF-beta. Together these results demonstrate discrete, yet significant and highly specific, regulation of fibroblast functions important for wound healing by basal JNK activity.
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https://www.hal.inserm.fr/inserm-00147462
Contributor : Alain Mauviel <>
Submitted on : Monday, May 21, 2007 - 2:48:22 PM
Last modification on : Monday, May 21, 2007 - 2:48:22 PM
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Delphine Javelaud, Julien Laboureau, Eric Gabison, Franck Verrecchia, Alain Mauviel. Disruption of basal JNK activity differentially affects key fibroblast functions important for wound healing.: Basal JNK activity regulates fibroblast functions. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2003, 278 (27), pp.24624-8. ⟨10.1074/jbc.M301942200⟩. ⟨inserm-00147462⟩

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