Caspase 2 is both required for p53-mediated apoptosis and downregulated by p53 in a p21-dependent manner

Cell Cycle. 2008 May 1;7(9):1133-8. doi: 10.4161/cc.7.9.5805. Epub 2008 Feb 19.


Upon treatment with some DNA damaging agents, human H1299 tumor-derived cells expressing inducible versions of wild-type or mutant p53 with inactive transactivation domain I (p53(Q22/S23)) undergo apoptosis. In cells expressing either version of p53, caspase 2 activation is required for release of cytochrome c and cell death. Furthermore, silencing of PIDD (a factor previously shown to be required for caspase 2 activation) by siRNA suppresses apoptosis by both wild-type p53 and p53(Q22/S23). Despite the finding that caspase 2 is essential for DNA damage-facilitated, p53-mediated apoptosis, induction of wild-type p53 (with or without DNA damage) resulted in a reduction of caspase 2 mRNA and protein levels. In this study we sought to provide a mechanism for the negative regulation of caspase 2 by p53 as well as provide insight as to why p53 may repress a key mediator of p53-dependent apoptosis. Mechanistically, we show that DNA binding and/or transactivation domains of p53 are crucial for mediating transrepression. Further, expression of p21 (in p53-null cells inducibly expressing p21) is sufficient to mediate repression of caspase 2. Deletion of p21 or E2F-1 not only abrogated repression of caspase 2, but also stimulated the expression of caspase 2 above basal levels, implicating the requirement for an intact p21/Rb/E2F pathway in the downregulation of caspase 2. As this p53/p21-dependent repression of caspase 2 can occur in the absence of DNA damage, caspase 2 repression does not simply seem to be a consequence of the apoptotic process. Downregulation of caspase 2 levels by p53 may help to determine cell fate by preventing cell death when unnecessary.

MeSH terms

  • Apoptosis / physiology*
  • Binding Sites / physiology
  • Caspase 2 / genetics
  • Caspase 2 / metabolism*
  • Cell Death / physiology
  • Cell Line
  • Cell Lineage / physiology
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / physiology*
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism
  • Humans
  • Protein Structure, Tertiary / physiology
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*


  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins
  • E2F1 Transcription Factor
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • CASP2 protein, human
  • Caspase 2
  • Cysteine Endopeptidases