title: Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-alpha: CrmA and Bcl-2 target distinct components in the apoptotic pathway.
abstract: Proteases are now firmly established as major regulators of the "execution" phase of apoptosis. Here, we examine the role of proteases and their relationship to ceramide, a proposed mediator of apoptosis, in the tumor necrosis factor-alpha (TNF-alpha)-induced pathway of cell death. Ceramide induced activation of prICE, the protease that cleaves the death substrate poly(ADP-ribose) polymerase. Bcl-2 inhibited ceramide-induced death, but not ceramide generation. In contrast, Cytokine response modifier A (CrmA), a potent inhibitor of Interleukin-1 beta converting enzyme and related proteases, inhibited ceramide generation and prevented TNF-alpha-induced death. Exogenous ceramide could overcome the CrmA block to cell death, but not the Bcl-2 block. CrmA, however, did not inhibit the activation of nuclear factor (NF)-kappa B by TNF-alpha, demonstrating that other signaling functions of TNF-alpha remain intact and that ceramide does not play a role in the activation of NF-kappa B. These studies support a distinct role for proteases in the signaling/activation phase of apoptosis acting upstream of ceramide formation.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Dbaibo
authors.forename: D K
authors.initials: DK
authors.lastname: Perry
authors.forename: C J
authors.initials: CJ
authors.lastname: Gamard
authors.forename: R
authors.initials: R
authors.lastname: Platt
authors.forename: G G
authors.initials: GG
authors.lastname: Poirier
authors.forename: L M
authors.initials: LM
authors.lastname: Obeid
authors.forename: Y A
authors.initials: YA
authors.lastname: Hannun
mesh_terms: D017209:Apoptosis; D002518:Ceramides / Q000096:biosynthesis*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D015843:Serpins / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014764:Viral Proteins
chemical_list: D002518:Ceramides; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D011065:Poly(ADP-ribose) Polymerases