title: Interaction and stabilization of X-linked inhibitor of apoptosis by Raf-1 protein kinase.
abstract: Raf-1 serine/threonine protein kinase plays an important role in cell growth, differentiation and cell survival. Recent reports using c-raf-1 gene-knockouts have observed MEK/ERK independent functions of Raf-1 in cell survival and protection from apoptosis. Raf-1 has also been shown to be involved in counteracting specific apoptotic pathways by restraining caspase activation, although the precise mechanism is unknown. XIAP is a potent inhibitor of apoptosis that blocks both the mitochondria and death receptor mediated pathways of apoptosis by directly binding to and inhibiting the initiator and effector caspases. In our efforts to understand the mechanism by which Raf-1 inhibits caspase activation, we discovered a novel interaction between Raf-1 and XIAP. In this study, we describe the physical interaction between Raf-1 and XIAP in vitro and in vivo in mammalian cells. We also demonstrate that Raf-1 phosphorylates XIAP in vitro and in vivo. Additionally, Raf-1 prevents XIAP degradation in response to different apoptotic triggers. Our studies identify XIAP as a new substrate of Raf-1 and provide potentially important insight into mechanisms underlying Raf-1 effects on cell survival.
authors.affiliation: Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Tian
authors.forename: Rajshree R
authors.initials: RR
authors.lastname: Mewani
authors.forename: Deepak
authors.initials: D
authors.lastname: Kumar
authors.forename: Bihua
authors.initials: B
authors.lastname: Li
authors.forename: Malika T
authors.initials: MT
authors.lastname: Danner
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
authors.forename: Aquilur
authors.initials: A
authors.lastname: Rahman
authors.forename: Vicente
authors.initials: V
authors.lastname: Notario
authors.forename: Anatoly
authors.initials: A
authors.lastname: Dritschilo
authors.forename: Usha N
authors.initials: UN
authors.lastname: Kasid
authors.forename: Prafulla C
authors.initials: PC
authors.lastname: Gokhale
mesh_terms: D017209:Apoptosis; D006801:Humans; D047468:Immunoprecipitation; D019908:Proto-Oncogene Proteins c-raf / Q000032:analysis / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000032:analysis / Q000378:metabolism*
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein; D019908:Proto-Oncogene Proteins c-raf