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

Curr Biol. 2000 Nov 2;10(21):1359-66. doi: 10.1016/s0960-9822(00)00781-8.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Antineoplastic Agents
  • BIRC7 protein, human
  • Carrier Proteins
  • Caspase Inhibitors
  • Inhibitor of Apoptosis Proteins
  • Neoplasm Proteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • fas Receptor
  • Doxorubicin
  • Caspases