Livin, a Novel Inhibitor of Apoptosis Protein Family Member

Kasof, Gary M.; Gomes, Bruce

doi:10.1074/jbc.m003670200

Cited by 421 publications

(387 citation statements)

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“…PLAUR and SERPINE1 are components of the urokinase plasminogen activator system, and the overexpression of these genes has been correlated with a high-grade tumor and poor survival outcomes in RCC (Swiercz et al, 1998;Ohba et al, 2005). Livin is a member of the inhibitor of apoptosis protein family and can limit apoptosis by inhibiting the proteolytic activation of CXXC4 and progression of RCC T Kojima et al caspases 3, 7 and 9 (Kasof and Gomes, 2001). In RCC, Livin expression was significantly increased in the tumor tissues , and BIRC7 RNAi sensitized these RCC cells to proapoptotic stimuli .…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

et al. 2008

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The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P ¼ 0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P ¼ 0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of b-catenin. Knockdown of CXXC4 induced the nuclear translocation of b-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

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Section: Discussionmentioning

confidence: 99%

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

et al. 2008

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“…Kasof and Gomes 16 reported that Livin was able to prevent HeLa cells from apoptosis induced by RIP3; we therefore compared the antiapoptotic ability of wt-Livin and Livin BIR mutants in preventing RIP3-induced apoptosis. As shown in Figures 3, 4a-1, the BIR mutants expression level is lower than that of the wt-Livin.…”

Section: Mutation In Livin Bir Domain Enhances Its Degradation and Rementioning

confidence: 99%

“…15 It has not yet been demonstrated, however, if this is generally true for all RING domain-containing IAP family members. Livin, also called KIAP and ML-IAP, [16][17][18] encodes a protein with a single BIR domain and a carboxy-terminal RING domain. Recent reports have demonstrated that Livin can interact via its BIR domain with caspase-3 and -7 in vitro and caspase-9 and Smac/DIABLO in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Recent reports have demonstrated that Livin can interact via its BIR domain with caspase-3 and -7 in vitro and caspase-9 and Smac/DIABLO in vivo. 9,16 Disruption of interaction between Livin and Smac/DIABLO abrogated the ability of Livin to inhibit apoptosis. Yang and Du 19 reported that although Smac/ DIABLO can efficiently promote the auto-ubiquitination of Livin, it was unable to target Livin for rapid degradation in HeLa cells.…”

Section: Introductionmentioning

confidence: 99%

“…Although Livin was reported to be a poor caspase inhibitor, it can nonetheless protect cells from apoptosis induced by multiple death stimuli such as FADD, Bax, RIP, RIP3 and DR6. 16 This gives rise to the possibility that Livin may exert its antiapoptotic properties by as yet uncharacterized caspase-independent mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Livin promotes Smac/DIABLO degradation by ubiquitin–proteasome pathway

Huang

Song

et al. 2006

Cell Death Differ

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Livin, a member of the inhibitor of apoptosis protein (IAP) family, encodes a protein containing a single baculoviral IAP repeat (BIR) domain and a COOH-terminal RING finger domain. 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. Nonetheless, the detailed mechanism underlying its antiapoptotic function has not yet been fully characterized. In this report, we provide, for the first time, the evidence that Livin can act as an E3 ubiquitin ligase for targeting the degradation of Smac/ DIABLO. Both BIR domain and RING finger domain of Livin are required for this degradation in vitro and in vivo. We also demonstrate that Livin is an unstable protein with a half-life of less than 4 h in living cells. The RING domain of Livin promotes its auto-ubiquitination, whereas the BIR domain is likely to display degradation-inhibitory activity. Mutation in the Livin BIR domain greatly enhances its instability and nullifies its binding to Smac/DIABLO, resulting in a reduced antiapoptosis inhibition. Our findings provide a novel function of Livin: it exhibits E3 ubiquitin ligase activity to degrade the pivotal apoptotic regulator Smac/DIABLO through the ubiquitin-proteasome pathway.

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Inhibitor of Apoptosis ( IAP ) and BIR ‐containing Proteins

Vaux

2009

Encyclopedia of Life Sciences

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The inhibitor of apoptosis (IAP) family of proteins are characterized by presence of one or more baculoviral IAP Repeat (BIR) domains, so they are also termed BIRCs, for ‘BIR‐containing’ proteins. The first IAPs were identified in insect‐attacking viruses, which use them to inhibit defensive apoptosis of the host cell. Subsequently, other BIR‐containing proteins have been found in organisms from yeasts to mammals. The human IAP XIAP can block apoptosis by directly inhibiting caspases, whereas cIAP1 and cIAP2 inhibit apoptosis by reducing caspase‐activating signals from tumour necrosis factor (TNF) receptor superfamily members. As the genes for some IAPs are amplified in cancers, they appear to be able to act as oncogenes. IAP‐antagonist compounds modelled on the IAP antagonist Smac/Diablo are being developed for the treatment of cancer, and are currently undergoing clinical trials. Key concepts All IAPs bear at least one BIR domain, but not all BIR‐containing proteins are inhibitors of apoptosis. XIAP can block apoptosis by directly inhibiting caspases, but cIAP1 and cIAP2 inhibit apoptosis by reducing caspase‐activating signals from TNF receptor superfamily members, and by promoting activation of canonical NFκB pathways rather than noncanonical NFκB pathways. Genes for some IAPs are amplified in cancers, and IAP‐antagonist compounds modelled on the IAP antagonist Smac/Diablo are being developed for the treatment of cancer. Survivin and BRUCE are not apoptosis inhibitors, but are needed for cell division.

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Livin, a Novel Inhibitor of Apoptosis Protein Family Member

Cited by 421 publications

References 41 publications

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

Livin promotes Smac/DIABLO degradation by ubiquitin–proteasome pathway

Inhibitor of Apoptosis ( IAP ) and BIR ‐containing Proteins

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