Caspase 10 levels are increased following DNA damage in a p53-dependent manner.
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.
Rikhof
Bart
B
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.
Corn
Paul G
PG
El-Deiry
Wafik S
WS
D000256:Adenoviridae / Q000235:genetics; D015153:Blotting, Western; D053455:Caspase 10; D020169:Caspases / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D012516:Osteosarcoma / Q000473:pathology; D010051:Ovarian Neoplasms / Q000473:pathology; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D053455:Caspase 10; D020169:Caspases; C506438:CASP10 protein, human