title: Interdependence of Bad and Puma during ionizing-radiation-induced apoptosis.
abstract: Ionizing radiation (IR)-induced DNA double-strand breaks trigger an extensive cellular signaling response that involves the coordination of hundreds of proteins to regulate DNA repair, cell cycle arrest and apoptotic pathways. The cellular outcome often depends on the level of DNA damage as well as the particular cell type. Proliferating zebrafish embryonic neurons are highly sensitive to IR-induced apoptosis, and both p53 and its transcriptional target puma are essential mediators of the response. The BH3-only protein Puma has previously been reported to activate mitochondrial apoptosis through direct interaction with the pro-apoptotic Bcl-2 family proteins Bax and Bak, thus constituting the role of an "activator" BH3-only protein. This distinguishes it from BH3-only proteins like Bad that are thought to indirectly promote apoptosis through binding to anti-apoptotic Bcl-2 family members, thereby preventing the sequestration of activator BH3-only proteins and allowing them to directly interact with and activate Bax and Bak. We have shown previously that overexpression of the BH3-only protein Bad in zebrafish embryos supports normal embryonic development but greatly sensitizes developing neurons to IR-induced apoptosis. While Bad has previously been shown to play only a minor role in promoting IR-induced apoptosis of T cells in mice, we demonstrate that Bad is essential for robust IR-induced apoptosis in zebrafish embryonic neural tissue. Moreover, we found that both p53 and Puma are required for Bad-mediated radiosensitization in vivo. Our findings show the existence of a hierarchical interdependence between Bad and Puma whereby Bad functions as an essential sensitizer and Puma as an essential activator of IR-induced mitochondrial apoptosis specifically in embryonic neural tissue.
authors: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors: Cristhian
authors: C
authors: Toruno
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Seth
authors: S
authors: Carbonneau
authors: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors: Rodney A
authors: RA
authors: Stewart
authors: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors: Cicely
authors: C
authors: Jette
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008957:Models, Genetic; D009417:Nerve Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000077191:Wortmannin; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: D000730:Androstadienes; D051017:Apoptosis Regulatory Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C494818:badb protein, zebrafish; C553190:bbc3 protein, zebrafish; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D000077191:Wortmannin