Journal article
Essential role for Bim in mediating the apoptotic and antitumor activities of immunotoxins
A Antignani, D Segal, N Simon, RJ Kreitman, D Huang, DJ Fitzgerald
Oncogene | NATURE PUBLISHING GROUP | Published : 2017
DOI: 10.1038/onc.2017.111
Abstract
Protein synthesis is crucial for regulating cell homeostasis and, when unrestricted, it can lead to tumorigenesis. Immunotoxins derived from Pseudomonas exotoxin are antibody-toxin fusion proteins that inhibit protein synthesis of mammalian cells via ADP-ribosylation of the eukaryotic elongation factor-2. Here we investigate the role of the Bcl-2 family proteins in the response of cancer cells to immunotoxin challenge. Besides the well-known reduction of the prosurvival Bcl-2 family member, Mcl-1, following inhibition of protein synthesis, we show for the first time that immunotoxins also reduce the levels of selected proapoptotic BH-3-only proteins. Among these, only Bim protein levels corr..
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Awarded by National Institutes of Health
Funding Acknowledgements
The authors thank R Anderson and W Welch for the gift of reagents and Jianan Gong and Stephen Wilcox for assistance with sequence validation of CRISPR/Cas9 knockout cell lines. We thank E Arons for advice on the RT-PCR. This work was funded by the intramural programs of the National Cancer Institute, NIH and is supported by fellowships, and grants from the Australian National Health and Medical Research Council (research fellowships to DCSH; project grant 1057742 (DCSH); program grant 1016701; and Independent Research Institutes Infrastructure Support Scheme (grant 9000220)), the Cancer Council Victoria (grant-in-aid to DCSH), the Leukemia and Lymphoma Society (Specialized Centers of Research grants 7001-13), the Australian Cancer Research Foundation, a Victorian State Government Operational Infrastructure Support grant.