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 RIS Download
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