Caspase 2 is both required for p53-mediated apoptosis and downregulated by p53 in a p21-dependent manner.
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.
Baptiste-Okoh
Nicole
N
Department of Biological Sciences, Columbia University, New York, New York, USA.
Barsotti
Anthony M
AM
Prives
Carol
C
D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites / Q000502:physiology; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D019070:Cell Lineage / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017434:Protein Structure, Tertiary / Q000502:physiology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases