TWEAK affects keratinocyte G2/M growth arrest and induces apoptosis through the translocation of the AIF protein to the nucleus

PLoS One. 2012;7(3):e33609. doi: 10.1371/journal.pone.0033609. Epub 2012 Mar 16.


The soluble TNF-like weak inducer of apoptosis (TWEAK, TNFSF12) binds to the fibroblast growth factor-inducible 14 receptor (FN14, TNFRSF12A) on the cell membrane and induces multiple biological responses, such as proliferation, migration, differentiation, angiogenesis and apoptosis. Previous reports show that TWEAK, which does not contain a death domain in its cytoplasmic tail, induces the apoptosis of tumor cell lines through the induction of TNFα secretion. TWEAK induces apoptosis in human keratinocytes. Our experiments clearly demonstrate that TWEAK does not induce the secretion of TNFα or TRAIL proteins. The use of specific inhibitors and the absence of procaspase-3 cleavage suggest that the apoptosis of keratinocytes follows a caspase- and cathepsin B-independent pathway. Further investigation showed that TWEAK induces a decrease in the mitochondrial membrane potential of keratinocytes. Confocal microscopy showed that TWEAK induces the cleavage and the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus, thus initiating caspase-independent apoptosis. Moreover, TWEAK induces FOXO3 and GADD45 expression, cdc2 phosphorylation and cdc2 and cyclinB1 degradation, resulting in the arrest of cell growth at the G2/M phase. Finally, we report that TWEAK and FN14 are normally expressed in the basal layer of the physiological epidermis and are greatly enhanced in benign (psoriasis) and malignant (squamous cell carcinoma) skin pathologies that are characterized by an inflammatory component. TWEAK might play an essential role in skin homeostasis and pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Apoptosis / physiology*
  • Apoptosis Inducing Factor / metabolism*
  • CDC2 Protein Kinase
  • Caspases / metabolism
  • Cathepsin B / metabolism
  • Cell Line
  • Cyclin B / metabolism
  • Cyclin B1 / metabolism
  • Cyclin-Dependent Kinases
  • Cytokine TWEAK
  • G2 Phase Cell Cycle Checkpoints / physiology*
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Keratinocytes / cytology*
  • Keratinocytes / metabolism*
  • Psoriasis / metabolism
  • Psoriasis / pathology
  • Receptors, Tumor Necrosis Factor / metabolism
  • Skin / cytology
  • Skin / metabolism
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • TNF-Related Apoptosis-Inducing Ligand / biosynthesis
  • TWEAK Receptor
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factors / metabolism*


  • AIFM1 protein, human
  • Apoptosis Inducing Factor
  • CCNB1 protein, human
  • Cyclin B
  • Cyclin B1
  • Cytokine TWEAK
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF12A protein, human
  • TNFSF10 protein, human
  • TNFSF12 protein, human
  • TWEAK Receptor
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factors
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases
  • Caspases
  • CTSB protein, human
  • Cathepsin B