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Caspases and mitochondria in c-Myc-induced apoptosis: identification of ATM as a new target of caspases

Abstract

The mechanism(s) of c-Myc transcription factor-induced apoptosis is still obscure. The activation of c-Myc has been found to lead into the processing/activation of caspases (caspase-3), but the significance of this for the cell demise is debatable. Here we report that several targets of caspases (PKCδ, MDM2, PARP, replication factor C, 70 kDa U1snRNP, fodrin and lamins) are cleaved during c-Myc-induced apoptosis in Rat-1 MycERTM cells, indicating an important role for caspases in the apoptotic process. We further found that the ATM (ataxia telangiectasia mutated) – protein is a novel key substrate of caspases. In in vitro assays, purified recombinant ATM protein was found to be cleaved by the effector caspases 3 and 7. The functional significance of the ATM cleavage is supported by the finding that ectopic expression of ATM protected in part against apoptosis. We also show that c-Myc-induced apoptosis involves loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria into the cytosol and subsequent processing of caspase-9. The cleavage of caspase-9 is, however, minimal and a much later event than the processing/activation of caspase-3, suggesting that it is not the apical caspase. Evidence is provided that there is, nevertheless, an upstream caspase(s) regulating the functions of caspase-3 and mitochondria. Additionally, it was found that p53 becomes upregulated, together with its transcriptional targets MDM2 and p21, upon c-Myc induction, but this occurs also at a later time than the activation of caspase-3.

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Acknowledgements

Drs Dennis Danley, Guy G Poirier, Anthony Rosen, Wolfgang Schmid, Claudio Schneider, Donald Nicholson, Razquallah Hakem, Tak Mak and Ismo Virtanen are warmly thanked for providing us with antibodies and Dr Yosef Shiloh for the bacterial strains of the pEBS7 and pEBS7-YZ5 vectors. Ms Monica Schoulz is thanked for the FACS analysis. This work was supported by the University of Helsinki, the Finnish Cancer Organizations, the Ida Montin Foundation, the Research and Science Foundation of Farmos, the Finnish Life and Pension Insurance Companies and the Finnish Academy of Sciences.

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Hotti, A., Järvinen, K., Siivola, P. et al. Caspases and mitochondria in c-Myc-induced apoptosis: identification of ATM as a new target of caspases. Oncogene 19, 2354–2362 (2000). https://doi.org/10.1038/sj.onc.1203567

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