title: Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway.
abstract: Stimulation of death receptors by agonists such as FasL and TNFalpha activates apoptotic cell death in apoptotic-competent conditions or a type of necrotic cell death dependent on RIP1 kinase, termed necroptosis, in apoptotic-deficient conditions. In a genome-wide siRNA screen for regulators of necroptosis, we identify a set of 432 genes that regulate necroptosis, a subset of 32 genes that act downstream and/or as regulators of RIP1 kinase, 32 genes required for death-receptor-mediated apoptosis, and 7 genes involved in both necroptosis and apoptosis. We show that the expression of subsets of the 432 genes is enriched in the immune and nervous systems, and cellular sensitivity to necroptosis is regulated by an extensive signaling network mediating innate immunity. Interestingly, Bmf, a BH3-only Bcl-2 family member, is required for death-receptor-induced necroptosis. Our study defines a cellular signaling network that regulates necroptosis and the molecular bifurcation that controls apoptosis and necroptosis.
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Hitomi
authors.forename: Dana E
authors.initials: DE
authors.lastname: Christofferson
authors.forename: Aylwin
authors.initials: A
authors.lastname: Ng
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yao
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D020869:Gene Expression Profiling; D016678:Genome; D006801:Humans; D051379:Mice; D009336:Necrosis; D009857:Oncogenes; D014176:Protein Biosynthesis; D025941:Protein Interaction Mapping; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing