title: Modulation of cell death in yeast by the Bcl-2 family of proteins.
abstract: Bcl-2 family members are regulators of cell death. The precise biochemical properties of these proteins are unclear although intrafamily protein-protein association is thought to be involved. To elucidate structure-activity relationships among Bcl-2 proteins and identify the pathways in which they act, an inducible death suppressor assay was developed in yeast. Only Bax and Bak killed yeast via a process that did not require interleukin-1beta-converting enzyme-like proteases. Bax/Bak lethality was suppressed by coexpression of Bcl-2 family members that are anti-apoptotic in vertebrates, namely Bcl-xL, Bcl-2, Mcl-1, and A1. Furthermore, Bcl-xL and Bcl-2 suppressed Bax toxicity by distinct mechanisms in yeast. Bad, Bcl-xS, and Ced-9 lacked suppressor activity. These inactive proteins bound to anti-apoptotic members of the Bcl-2 family but not to Bax or Bak. In contrast, most Bcl-2 family proteins that attenuated death bound to Bax and Bak. However, two mutants of Bcl-xL suppressed Bax-induced cell death while having no Bax binding activity. Therefore, Bcl-xL functions independently of Bax binding, perhaps by interacting with a common target or promoting a pathway that antagonizes Bax. Thus, the pathways downstream of Bax and Bcl-xL may be conserved between vertebrates and yeast. This suppressor assay could be used to isolate components of these pathways.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: W
authors.initials: W
authors.lastname: Tao
authors.forename: C
authors.initials: C
authors.lastname: Kurschner
authors.forename: J I
authors.initials: JI
authors.lastname: Morgan
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D005786:Gene Expression Regulation; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000166:cytology*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2