Disease relevance of BIRC7

• SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP) [1].
• Expression of BIRC7 protein and mRNA in non-Hodgkin's lymphoma [2].
• BIRC7 protein was exhibited in the cytoplasm of cells in 25 (31%) of 80 cases of B-NHLs, 32 (37%) of 87 cases of T-NHLs, and none in non-specific lymphadenitis [2].
• However, there are no reported data concerning BIRC7 expression in lymphomas [2].
• One member protein of the inhibitor of apoptosis protein (IAP) family, Livin, was selectively expressed in the malignant cells at higher levels, particularly in T-ALL CD4(+) T cells, in comparison with the expression in CD4 and CD8 double-positive thymocytes [3].
• Targeted inhibition of livin could represent a novel therapeutic strategy to increase the sensitivity of renal cancers towards pro-apoptotic agents [4].

High impact information on BIRC7

• This protection is associated with cAMP-mediated, rapid induction of cellular inhibitor of apoptosis protein (c-IAP)-2 and delayed induction of LIVIN, but not of six other members of the IAP family [5].
• Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction [6].
• Whereas melanoma cells in densely infiltrated lesions showed strong ML-IAP expression by immunohistochemistry, lethal disease progression was associated with the loss of ML-IAP staining and the absence of lymphocyte infiltrates [6].
• Moreover, lymphocyte infiltrates in necrotic metastases included CD4+ and CD8+ T cells specific for ML-IAP, as revealed by proliferation, tetramer, enzyme-linked immunospot, and cytotoxicity analysis [6].
• Although K030 harbored antibodies to ML-IAP at the time of study entry, multiple courses of vaccination over 4 years increased antibody titers and elicited isotype switching [6].

Chemical compound and disease context of BIRC7

• RESULTS: Livin cleavage was observed in multiple human melanoma cell lines in response to a variety of apoptotic stimuli (UVB, 4-TBP, cisplatin, TNF, Bax), and not affected by the addition of various protease inhibitors or RNAi-mediated silencing of Omi/HtrA2 [7].

Biological context of BIRC7

• We identified vector-borne small interfering (si)RNAs, which could efficiently block endogenous livin gene expression [8].
• Thus, elevated expression of ML-IAP renders melanoma cells resistant to apoptotic stimuli and thereby potentially contributes to the oncogenic phenotype [9].
• We have identified a novel human gene, kiap (kidney inhibitor of apoptosis protein) that encodes a single BIR domain and a RING zinc finger domain. kiap has been assigned to the q13.3 region of human chromosome 20 by fluorescent in situ hybridization analysis [10].
• Intensity of anti-livin antibody responses did not correlate with intensity of anti-survivin responses [11].
• Mutational analysis of the ML-IAP-BIR domain demonstrated that similar enhancements in caspase 9 affinity can be achieved with only three amino acid substitutions [12].

Anatomical context of BIRC7

• BIRC7 mRNA in three cell lines and 16 cases of NHL were detected by reverse transcriptase-polymerase chain reaction [2].
• Studies have shown that BIRC7, a new member of inhibitor of the apoptosis protein family, is expressed in fetal tissues and most solid tumors in humans [2].
• In particular, the majority of melanoma cell lines expressed high levels of ML-IAP in contrast to primary melanocytes, which expressed undetectable levels [13].
• Northern blot analysis indicates that KIAP is expressed mainly in placenta, lymph node and fetal kidney [10].
• Moreover, although pro-apoptotic factors such as irradiation or anti-cancer drugs may release Smac from mitochondria in tumor cells, high cytoplasmic survivin and ML-IAP levels might be able to neutralize it and, consequently, IAPs would further be able to bind activated caspases [14].

Associations of BIRC7 with chemical compounds

• Silencing of livin was associated with caspase-3 activation and a strongly increased apoptotic rate in response to different proapoptotic stimuli, such as doxorubicin, UV-irradiation, or TNFalpha [8].
• In this report, we show that overexpression of KIAP blocks apoptosis induced by menadione or by overexpression of BAX [10].
• Curcumin determined early changes in COX-2 and c-myc mRNAs, which were down-regulated, and in livin mRNA, which was up-regulated [15].
• Dissociation constant (Kd) of VCR and apparent inhibitory constant (Kiapp) of verapamil were calculated to be 0.1 +/- 0.1 microM (SD) and 1 +/- 1 microM, respectively [16].
• Recombinant CDK4-cyclin D1 was inhibited potently by Flavopiridol (Kiapp, 65 nM), competitive with respect to ATP [17].

Physical interactions of BIRC7

• The X-ray crystal structure of this compound bound to an ML-IAP/XIAP chimeric BIR domain protein is compared with that of a complex with a phage-derived tetrapeptide, AVPW [18].
• The structures show that these compounds bind to the Smac-binding site on ML-IAP with identical hydrogen-bonding patterns and similar hydrophobic interactions [18].

Regulatory relationships of BIRC7

• It has been reported that Livin directly interacts with caspase-3 and -7 in vitro and caspase-9 in vivo via its BIR domain and is negatively regulated by Smac/DIABLO [19].
• CC chemokine ligand 25 enhances resistance to apoptosis in CD4+ T cells from patients with T-cell lineage acute and chronic lymphocytic leukemia by means of livin activation [3].
• These results suggest that (a) livin is expressed in primary and cultured neuroblastoma cells and (b) high livin expression may identify a subset of neuroblastoma patients with a particularly poor prognosis among those with MYCN amplified tumors [20].

Other interactions of BIRC7

• Here we report that two other members of the IAP family, NAIP and ML-IAP, both activate JNK1 [21].
• Only IAP-1 and livin protein was expressed in the nucleus of MPM tumours [22].
• After stimulation with CCL25 and apoptotic induction with TNF-alpha, the expression levels of Livin in these malignant cells were significantly increased [3].
• Levels of other IAPs were not altered in Survivin-targeted cells, although modest cleavage of XIAP and Livin was observed [23].
• When we evaluated the dependence between each gene expression and relapse free time of patients, we found that LIVIN, high BCL-2/BAX ratio and BCL-X(L), but not SURVIVIN, reached statistical significance in order to predict relapses [24].

Analytical, diagnostic and therapeutic context of BIRC7

• We investigated the expression of BIRC7, survivin, Bcl-2, Bax, p53 and p170 proteins in 167 cases of non-Hodgkin's lymphoma (NHL) and 10 cases of non-specific lymphadenitis by tissue microarray-based immunohistochemistry [2].
• The mRNA for livin was not detectable by Northern blot in most normal adult tissues with the exception of the placenta, but was present in developmental tissues and in several cancer cell lines [25].
• The subcellular distribution of the transfected Livin was analyzed by immunofluorescence [25].
• METHODS: Effusions (106) were analyzed for XIAP, Survivin, and Livin expression using immunoblotting [26].
• METHODS: We examined the prevalence of anti-survivin and livin antibodies in breast cancer patients with a specific enzyme-linked immunosorbent assay (ELISA) using recombinant protein [11].

References