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.
Vucic
D
D
Department of Molecular Oncology, Genentech Incorporated, 1 DNA Way, San Francisco, California 94080, USA.
Stennicke
H R
HR
Pisabarro
M T
MT
Salvesen
G S
GS
Dixit
V M
VM
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000970:Antineoplastic Agents; C419866:BIRC7 protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D019014:fas Receptor; D004317:Doxorubicin; D020169:Caspases