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ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas.

BACKGROUND: Inhibitors of apoptosis (IAPs) are a family of cell death inhibitors found in viruses and metazoans. All IAPs have at least one baculovirus IAP repeat (BIR) motif that is essential for their anti-apoptotic activity. IAPs physically interact with a variety of pro-apoptotic proteins and inhibit apoptosis induced by diverse stimuli. This allows them to function as sensors and inhibitors of death signals that emanate from a variety of pathways. RESULTS: Here we report the characterization of ML-IAP, a novel human IAP that contains a single BIR and RING finger motif. ML-IAP is a powerful inhibitor of apoptosis induced by death receptors and chemotherapeutic agents, probably functioning as a direct inhibitor of downstream effector caspases. Modeling studies of the structure of the BIR domain revealed it to closely resemble the fold determined for the BIR2 domain of X-IAP. Deletion and mutational analysis demonstrated that integrity of the BIR domain was required for anti-apoptotic function. Tissue survey analysis showed expression in a number of embryonic tissues and tumor cell lines. In particular, the majority of melanoma cell lines expressed high levels of ML-IAP in contrast to primary melanocytes, which expressed undetectable levels. These melanoma cells were significantly more resistant to drug-induced apoptosis. CONCLUSIONS: ML-IAP, a novel human IAP, inhibits apoptosis induced by death receptors and chemotherapeutic agents. The BIR of ML-IAP possesses an evolutionarily conserved fold that is necessary for anti-apoptotic activity. Elevated expression of ML-IAP renders melanoma cells resistant to apoptotic stimuli and thereby potentially contributes to the pathogenesis of this malignancy.

Pubmed ID: 11084335

Authors

  • Vucic D
  • Stennicke HR
  • Pisabarro MT
  • Salvesen GS
  • Dixit VM

Journal

Current biology : CB

Publication Data

November 2, 2000

Associated Grants

  • Agency: NIA NIH HHS, Id: AG15402

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Antigens, CD
  • Antigens, CD95
  • Antineoplastic Agents
  • Apoptosis
  • Carrier Proteins
  • Caspase Inhibitors
  • Caspases
  • Cell Line
  • Doxorubicin
  • Genes, Reporter
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Melanocytes
  • Melanoma
  • Microscopy, Fluorescence
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Neoplasm Proteins
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins
  • Sequence Alignment
  • Tumor Cells, Cultured