Alternative titles; symbols
HGNC Approved Gene Symbol: BIRC7
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38) : 20:63,235,905-63,240,495 (from NCBI)
Inhibitor of apoptosis proteins (IAPs) contain conserved, unique N-terminal baculovirus IAP repeats (BIRs) and usually a C-terminal RING finger domain. The BIR domain is essential for inhibitory activity and typically interacts with cysteine-containing aspartate-specific proteases (caspases, e.g., CASP3; 600636) or with APAF1 (602233), which together with cytochrome C (123970) mediates activation of CASP9 (602234). The RING finger domain sometimes enhances antiapoptotic activity but does not inhibit apoptosis alone.
By searching a sequence database for BIR-containing sequences, Vucic et al. (2000) identified cDNAs encoding BIRC7, which they termed MLIAP. The deduced 280- and 298-amino acid BIRC7 proteins each contain a single BIR domain and a RING finger motif. The BIR domain is most similar to the second and third BIRs of BIRC2 (601712), BIRC3 (601721), and BIRC4 (XIAP; 300079). Northern blot analysis revealed highest expression of 1.5- and 2.2-kb transcripts in melanomas, with lower expression in some lymphomas, fetal kidney, fetal liver, testis, and thymus; expression was not detected in normal melanocytes. Confocal microscopy showed localization predominantly to the cytoplasm and, unlike that of survivin (BIRC5; 603352), not to mitotic spindles.
Lin et al. (2000) also cloned BIRC7, which they called KIAP, by searching an EST database and using 5-prime and 3-prime RACE on a fetal kidney cDNA library. Like apollon (BIRC6; 605638) and survivin, the deduced 299-amino acid BIRC7 protein contains only 1 BIR motif with the signature 3 cysteines and 1 histidine. Northern blot analysis detected 1.4-, 2.2-, and 4.0-kb transcripts in placenta, lymph node, and fetal kidney; expression was not detected in other normal tissues tested.
Kasof and Gomes (2001) also cloned BIRC7, which they termed livin. The deduced 280-amino acid protein lacks the coiled-coil domain found in survivin but does have a RING finger. Northern blot analysis revealed expression of 1.4-, 2.0-, and 2.8-kb transcripts in placenta and fetal brain, as well as in melanomas and, to a lesser extent, in HeLa cells.
Functional analysis by Vucic et al. (2000) showed that expression of BIRC7 blocked apoptosis induced by engagement of FAS (134637), tumor necrosis factor receptor-1 (TNFR1; 191190), death receptor-4 (DR4; 603611), and DR5 (603612), as well as apoptosis induced by chemotherapeutic agents, with a potency comparable to that observed with BIRC2 and BIRC4. Further analysis indicated that MLIAP is active against CASP3 and the cytochrome C pathway but not against CASP7 (601761). Mutational analysis determined that the BIR domain is essential for antiapoptotic activity.
Lin et al. (2000) showed that BIRC7 blocked apoptosis induced by BAX (600040) induction of cytochrome C release from mitochondria. The authors also found that BIRC7 blocked apoptosis induced by chemotherapeutic agents, but in contrast to the findings of Vucic et al. (2000), it did not block apoptosis induced by FAS.
Kasof and Gomes (2001) demonstrated that, through its BIR domain, livin inhibited apoptosis mediated by DR6 and downstream adaptor proteins within the TNF/FAS pathway. This inhibition could be reversed by an antisense construct to livin. Immunoprecipitation and Western blot analysis indicated livin binds to CASP3, CASP7, and CASP9, but it only inhibits CASP9. In contrast to the findings of Vucic et al. (2000), immunofluorescence microscopy detected overexpressed livin in the nucleus and in a filamentous pattern in the cytoplasm, as observed with survivin.
The identification of antigens associated with tumor destruction is a major goal of cancer immunology. Vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (CSF2; 138960) generates potent, specific, and long-lasting antitumor immunity through improved tumor antigen presentation by dendritic cells and macrophages. A phase I clinical trial of this immunization strategy in patients with disseminated melanoma revealed the consistent induction in distant metastases of dense T- and B-cell infiltrates that effectuated substantial tumor necrosis and fibrosis (Soiffer et al., 1998). To delineate the target antigens of this vaccine-stimulated tumor destruction, Schmollinger et al. (2003) screened a melanoma cDNA expression library with postimmunization sera from a long-term responding patient. High-titer IgG antibodies recognized MLIAP. Although the patient harbored antibodies to this protein at the time of study entry, multiple courses of vaccination over 4 years increased antibody titers and elicited isotype switching. Moreover, lymphocyte infiltrates in necrotic metastases included CD4(+) and CD8(+) T cells specific for MLIAP, as revealed by proliferation, tetramer, enzyme-linked immunospot, and cytotoxicity analysis. Whereas melanoma cells in densely infiltrated lesions showed strong MLIAP expression by immunohistochemistry, lethal disease progression was associated with the loss of MLIAP staining and the absence of lymphocyte infiltrates. These findings demonstrated that MLIAP can serve as a target for immune-mediated tumor destruction, but that antigen-loss variants can lead to immune escape.
Ye et al. (2013) found that microRNA-198 (MIR198; 605547) downregulated livin expression in human prostate cancer cells by directly binding to the livin 3-prime UTR.
Vucic et al. (2000) mapped the BIRC7 gene to 20q13, a region frequently amplified in melanomas and other malignancies, using radiation hybrid analysis. By FISH, Lin et al. (2000) localized the BIRC7 gene to 20q13.3.
Kasof, G. M., Gomes, B. C. Livin, a novel inhibitor of apoptosis protein family member. J. Biol. Chem. 276: 3238-3246, 2001. [PubMed: 11024045] [Full Text: https://doi.org/10.1074/jbc.M003670200]
Lin, J.-H., Deng, G., Huang, Q., Morser, J. KIAP, a novel member of the inhibitor of apoptosis protein family. Biochem. Biophys. Res. Commun. 279: 820-831, 2000. [PubMed: 11162435] [Full Text: https://doi.org/10.1006/bbrc.2000.4027]
Schmollinger, J. C., Vonderheide, R. H., Hoar, K. M., Maecker, B., Schultze, J. L., Hodi, F. S., Soiffer, R. J., Jung, K., Kuroda, M. J., Letvin, N. L., Greenfield, E. A., Mihm, M., Kutok, J. L., Dranoff, G. Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction. Proc. Nat. Acad. Sci. 100: 3398-3403, 2003. [PubMed: 12626761] [Full Text: https://doi.org/10.1073/pnas.0530311100]
Soiffer, R., Lynch, T., Mihm, M., Jung, K., Rhuda, C., Schmollinger, J. C., Hodi, F. S., Liebster, L., Lam, P., Mentzer, S., Singer, S., Tanabe, K. K., and 15 others. Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc. Nat. Acad. Sci. 95: 13141-13146, 1998. [PubMed: 9789055] [Full Text: https://doi.org/10.1073/pnas.95.22.13141]
Vucic, D., Stennicke, H. R., Pisabarro, M. T., Salvesen, G. S., Dixit, V. M. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr. Biol. 10: 1359-1366, 2000. [PubMed: 11084335] [Full Text: https://doi.org/10.1016/s0960-9822(00)00781-8]
Ye, L., Li, S., Ye, D., Yang, D., Yue, F., Guo, Y., Chen, X., Chen, F., Zhang, J., Song, X. Livin expression may be regulated by miR-198 in human prostate cancer cell lines. Europ. J. Cancer 49: 734-740, 2013. [PubMed: 23069480] [Full Text: https://doi.org/10.1016/j.ejca.2012.08.029]