title: BIM is the primary mediator of MYC-induced apoptosis in multiple solid tissues.
abstract: MYC is one of the most frequently overexpressed oncogenes in human cancer, and even modestly deregulated MYC can initiate ectopic proliferation in many postmitotic cell types in vivo. Sensitization of cells to apoptosis limits MYC's oncogenic potential. However, the mechanism through which MYC induces apoptosis is controversial. Some studies implicate p19ARF-mediated stabilization of p53, followed by induction of proapoptotic BH3 proteins NOXA and PUMA, whereas others argue for direct regulation of BH3 proteins, especially BIM. Here, we use a single experimental system to systematically evaluate the roles of p19ARF and BIM during MYC-induced apoptosis, in vitro, in vivo, and in combination with a widely used chemotherapeutic, doxorubicin. We find a common specific requirement for BIM during MYC-induced apoptosis in multiple settings, which does not extend to the p53-responsive BH3 family member PUMA, and find no evidence of a role for p19ARF during MYC-induced apoptosis in the tissues examined.
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Nathiya
authors.initials: N
authors.lastname: Muthalagu
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 2356 Sutter Street, San Francisco, CA 94115, USA.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Junttila
authors.affiliation: Theodor Boveri Institute, Biocentre, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Wiese
authors.affiliation: Theodor Boveri Institute, Biocentre, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Morton
authors.affiliation: Theodor Boveri Institute, Biocentre, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bauer
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 2356 Sutter Street, San Francisco, CA 94115, USA.
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.affiliation: Theodor Boveri Institute, Biocentre, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Theodor Boveri Institute, Biocentre, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. Electronic address: daniel.murphy@glasgow.ac.uk.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008565:Membrane Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin