The genetic depletion or the triptolide inhibition of TFIIH in p53-deficient cells induces a JNK-dependent cell death in Drosophila

J Cell Sci. 2013 Jun 1;126(Pt 11):2502-15. doi: 10.1242/jcs.122721. Epub 2013 Apr 2.

Abstract

Transcription factor IIH (TFIIH) participates in transcription, nucleotide excision repair and the control of the cell cycle. In the present study, we demonstrate that the Dmp52 subunit of TFIIH in Drosophila physically interacts with the fly p53 homologue, Dp53. The depletion of Dmp52 in the wing disc generates chromosome fragility, increases apoptosis and produces wings with a reduced number of cells; cellular proliferation, however, is not affected. Interestingly, instead of suppressing the apoptotic phenotype, the depletion of Dp53 in Dmp52-depleted wing disc cells increases apoptosis and the number of cells that suffer from chromosome fragility. The apoptosis induced by the depletion of Dmp52 alone is partially dependent on the JNK pathway. In contrast, the enhanced apoptosis caused by the simultaneous depletion of Dp53 and Dmp52 is absolutely JNK-dependent. In this study, we also show that the anti-proliferative drug triptolide, which inhibits the ATPase activity of the XPB subunit of TFIIH, phenocopies the JNK-dependent massive apoptotic phenotype of Dp53-depleted wing disc cells; this observation suggests that the mechanism by which triptolide induces apoptosis in p53-deficient cancer cells involves the activation of the JNK death pathway.

Keywords: Apoptosis; Drosophila; JNK; TFIIH; Triptolide; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Chromosome Fragility / drug effects
  • Chromosome Fragility / genetics
  • Chromosomes, Insect / genetics
  • Chromosomes, Insect / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Diterpenes / pharmacology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Epoxy Compounds / pharmacology
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Phenanthrenes / pharmacology*
  • Transcription Factor TFIIH / genetics
  • Transcription Factor TFIIH / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antineoplastic Agents, Alkylating
  • DNA-Binding Proteins
  • Diterpenes
  • Drosophila Proteins
  • Epoxy Compounds
  • Phenanthrenes
  • Tumor Suppressor Protein p53
  • Xbp1 protein, Drosophila
  • mrn protein, Drosophila
  • Transcription Factor TFIIH
  • triptolide
  • MAP Kinase Kinase 4