title: Bcl-2, via its BH4 domain, blocks apoptotic signaling mediated by mitochondrial Ras.
abstract: Bcl-2 protects cells against Ras-mediated apoptosis; this protection coincides with its binding to Ras. However, the protection mechanism has remained enigmatic. Here, we demonstrate that, upon apoptotic stimulation, newly synthesized Bcl-2 redistributes to mitochondria, interacts there with activated Ras, and blocks Ras-mediated apoptotic signaling. We also show, by employing bcl-2 mutants, that the BH4 domain of Bcl-2 binds to Ras and regulates its anti-apoptotic activity. Experiments with a C-terminal-truncated Ras or a farnesyltransferase inhibitor demonstrate that the CAAX motif of Ras is essential for apoptotic signaling and Bcl-2 association. The results indicate a potential mechanism by which Bcl-2 protects cells against Ras-mediated apoptotic signaling.
authors.affiliation: Cancer Research Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Gerald V
authors.initials: GV
authors.lastname: Denis
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
authors.forename: Peihong
authors.initials: P
authors.lastname: Ma
authors.forename: Linda
authors.initials: L
authors.lastname: Deeds
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Faller
authors.forename: Chang-Yan
authors.initials: CY
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites; D002051:Burkitt Lymphoma; D002458:Cell Fractionation / Q000379:methods; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000502:physiology*; D016296:Mutagenesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D018631:ras Proteins