title: A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling.
abstract: Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor alpha (TNFalpha) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNFalpha signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNFalpha induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNFalpha-mediated apoptosis.
authors: Oncology Disease Area and Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
authors: Alex
authors: A
authors: Gaither
authors: Dale
authors: D
authors: Porter
authors: Yao
authors: Y
authors: Yao
authors: Jason
authors: J
authors: Borawski
authors: Guang
authors: G
authors: Yang
authors: Jerry
authors: J
authors: Donovan
authors: David
authors: D
authors: Sage
authors: Joanna
authors: J
authors: Slisz
authors: Mary
authors: M
authors: Tran
authors: Christopher
authors: C
authors: Straub
authors: Tim
authors: T
authors: Ramsey
authors: Vadim
authors: V
authors: Iourgenko
authors: Alan
authors: A
authors: Huang
authors: Yan
authors: Y
authors: Chen
authors: Robert
authors: R
authors: Schlegel
authors: Mark
authors: M
authors: Labow
authors: Stephen
authors: S
authors: Fawell
authors: William R
authors: WR
authors: Sellers
authors: Leigh
authors: L
authors: Zawel
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D016923:Cell Death; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010051:Ovarian Neoplasms; D034622:RNA Interference / Q000502:physiology; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; C522798:LBW242; D024101:Mitochondrial Proteins; D009842:Oligopeptides; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human