Caspase 10 Levels are Increased Following DNA Damage in a p53-Dependent Manner

Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Departments of Medicine, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Cancer biology & therapy (Impact Factor: 3.07). 11/2003; 2(6):707-12. DOI: 10.4161/cbt.2.6.626
Source: PubMed


p53 plays a central role in the cellular response to stressful stimuli, including DNA damage, aberrant growth signals, and hypoxia. Upon activation, it binds to a specific DNA binding motif and functions to transcriptionally activate or repress different groups of genes. The biologic outcome of these events can lead to cell-cycle arrest, DNA repair, or apoptosis. While many downstream targets of p53 have been identified, the factors that determine which of these outcomes will occur in an individual cell are less clear. In this study, we show that caspase 10, an initiator caspase, is induced in response to DNA damaging chemotherapeutic agents in a p53-dependent manner. Following treatment with etoposide or adriamycin, induction of caspase 10 occurred at both the mRNA and protein levels. In contrast, DNA damage did not affect levels of caspase 8, another initiator caspase with significant structural and functional homology to caspase 10. By chromatin immunoprecipitation assay, p53 bound in vivo to multiple p53-specific binding sites located within the caspase 10 gene locus, suggesting that caspase 10 is a direct transcriptional target of p53. Upregulation of caspase 10 may represent one factor that determines how p53 activation leads to cellular apoptosis following DNA damage.

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    • "Activity of caspase-10 has been implicated in the response to a number of chemotherapeutic agents including etoposide, doxorubicin, arsenic trioxide and paclitaxel [18]–[20]. This can be mediated by p53-dependent, or histone-H3 acetylation-dependent modulation of the CASP10 locus [18]. "
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    PLoS ONE 07/2014; 9(7):e103383. DOI:10.1371/journal.pone.0103383 · 3.23 Impact Factor
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    • "It is well known that p53 is able to arrest the cell cycle, activate DNA repair proteins when DNA has sustained damage, and initiate apoptosis if the damage is irreparable [31,38]. To assess the hypothesis that MTA induces p53 expression caused by DNA damage, we studied the expression of p53 and related genes upon MTA exposure. "
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    • "Haefen et al (2003) [16] treated BJAB cells with paclitaxel which induced a 3/8 amplification feedback loop that is also similar to the CAAP regulated amplification loop, except that this 3/8 loop does not include caspase-10, whereas CAAP controls a loop including both caspase-8 and -10 as amplifying executioners. In addition, an in vivo analysis of programmed cell death of dorsal root ganglia neurons in mice demonstrated that the apoptotic pathway proceeded via a 3/9 feedback amplification loop [37]. Our identification of an ubiquitously expressed and evolutionary conserved CAAP gene as a negative modulator of the 3/9 feedback amplification loop requiring caspase-10 thus represents a novel pathway that might result in the development of new therapeutic strategies. "
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