title: Promotion and inhibition of activation-induced apoptosis in T-cell hybridomas by oncogenes and related signals.
abstract: The Two Signal: Death/Survival Model suggests that cellular proliferation and physiological cell death should be intimately associated such that, in the absence of external influences, a normal cell departing from rest will have an equal probability of undergoing either process. The c-Myc protooncogene product has been implicated in cell cycle progression and in the control of gene expression, and more recently c-Myc has also been seen to promote apoptotic cell death. As predicted from the model, c-Myc-induced apoptosis is inhibited by growth factors or other anti-apoptotic signals including those provided by some oncogenes. Here, we discuss experiments that test the Two Signal: Death/Survival Model in the phenomenon of activation-induced apoptosis in T-cell hybridomas. Ligation of the antigen receptor on these cells leads to activation, resulting in cytokine production and apoptosis. Inhibition of c-Myc expression by addition of antisense oligodeoxynucleotides or transforming growth factor beta inhibits this form of apoptosis. Because c-Myc is known to bind to several cellular proteins, including Max, we further examined the effects of expression of a dominant negative Max on activation-induced apoptosis. We found that this Max mutant, which interferes with the function of the Myc/Max heterodimer, inhibits the induction of apoptosis by antigen receptor ligation. Thus, both Myc and Max play roles in activation-induced apoptosis, presumably via control of gene expression. Further, as predicted, signals generated from growth factor receptors or the v-Abl oncogene interfere with activation-induced apoptosis. In contrast, the anti-apoptotic effects of Bcl-2 are not active in this form of apoptosis. Finally, a role for Fas/Fas-ligand interactions in activation-induced apoptosis is considered.
authors.affiliation: Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, CA 92037.
authors.forename: D R
authors.initials: DR
authors.lastname: Green
authors.forename: A
authors.initials: A
authors.lastname: Mahboubi
authors.forename: W
authors.initials: W
authors.lastname: Nishioka
authors.forename: S
authors.initials: S
authors.lastname: Oja
authors.forename: F
authors.initials: F
authors.lastname: Echeverri
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: J
authors.initials: J
authors.lastname: Glynn
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Ashwell
authors.forename: R
authors.initials: R
authors.lastname: Bissonnette
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D006825:Hybridomas / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc