Apoptotic threshold is lowered by p53 transactivation of caspase-6.
Little is known about how a cell's apoptotic threshold is controlled after exposure to chemotherapy, although the p53 tumor suppressor has been implicated. We identified executioner caspase-6 as a transcriptional target of p53. The mechanism involves DNA binding by p53 to the third intron of the caspase-6 gene and transactivation. A p53-dependent increase in procaspase-6 protein level allows for an increase in caspase-6 activity and caspase-6-specific Lamin A cleavage in response to Adriamycin exposure. Specific inhibition of caspase-6 blocks cell death in a manner that correlates with caspase-6 mRNA induction by p53 and enhances long-term survival in response to a p53-mediated apoptotic signal. Caspase-6 is an executioner caspase found directly regulated by p53, and the most downstream component of the death pathway controlled by p53. The induction of caspase-6 expression lowers the cell death threshold in response to apoptotic signals that activate caspase-6. Our results provide a potential mechanism of lowering the death threshold, which could be important for chemosensitization.
MacLachlan
Timothy K
TK
Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
El-Deiry
Wafik S
WS
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology*; D001483:Base Sequence; D053178:Caspase 6; D020169:Caspases / Q000096:biosynthesis* / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D018390:Gene Targeting; D016158:Genes, p53; D006801:Humans; D007763:Lac Operon; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology*
D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; C505514:CASP6 protein, human; D053178:Caspase 6; D020169:Caspases