Interchangeable binding of Bcl10 to TRAF2 and cIAPs regulates apoptosis signaling

Yui, Daishi; Yoneda, Takunari; Oono, Kayoko; Katayama, Taiichi; Imaizumi, Kazunori; Tohyama, Masaya

doi:10.1038/sj.onc.1204576

Cited by 23 publications

(28 citation statements)

References 27 publications

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“…80 On the other hand, BIRC3/cIAP2 can bind and mediate the ubiquitination and degradation of Bcl10, an activator of NFκB identified as a candidate gene responsible for low grade B cell lymphomas of mucosaassociated lymphoid tissue. 99,100 Concerning BIRC4/XIAP-mediated NFκB activation, two different mechanisms, dependent and independent of TAK-1, have been observed as reported above (Fig. 2).…”

Section: Iaps: Regulators Of Cell Signalingmentioning

confidence: 81%

“…90 In contrast to most IAPs, BIRC6/Bruce (mouse homolog of human Apollon) deficiency in mice causes embryonic and neonatal lethality. 21,22,100 A characterization of a phenotype of mutant embryos at different stages of gestation shows no remarkable abnormalities and no enhanced apoptotis rate, but growth retardation and a delay in erythrocyte maturation. 21,22 These effects could be secondary to an impaired placenta development.…”

Section: Iaps: Essential For Development and Differentiationmentioning

confidence: 99%

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IAPS : More than just inhibitors of apoptosis proteins

Dubrez

Dupoux²,

Cartier³

2008

Cell Cycle

190

170

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Inhibitors of apoptosis proteins (IAPs) are a conserved family of proteins identified in species ranging from virus, yeasts, nematodes, fishes, flies and mammals. The common structural feature is the presence of at least one Baculovirus IAP Repeat (BIR) domain. Hence, IAPs are also known as BIR-containing proteins (BIRCs). Most of them display anti-apoptotic properties when overexpressed. In drosophila, IAPs are sufficient and necessary to promote cell survival through a direct regulation of apoptotic proteases called caspases. In mammals, BIRC4/XIAP, the most studied IAP member can directly inhibit the activity of caspase-3, 7 and 9. However, this activity is not conserved in other IAPs and physiological relevancies of such anti-caspase activities are still discussed. A detailed analysis of IAP-deficient mice or derived cells, deletion experiments performed in drosophila and zebrafish, or research of protein partners have revealed the importance of IAPs in adaptive response to cellular stress, in cell proliferation, differentiation, signaling, motility and in immune response. This review discusses recent data that help understanding of cellular functions of IAPs.

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Section: Iaps: Regulators Of Cell Signalingmentioning

confidence: 81%

Section: Iaps: Essential For Development and Differentiationmentioning

confidence: 99%

IAPS : More than just inhibitors of apoptosis proteins

Dubrez

Dupoux²,

Cartier³

2008

Cell Cycle

190

170

View full text Add to dashboard Cite

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“…[39][40] The phosphorylation status of Bcl10 can apparently modulate cell apoptosis, possibly by regulating the binding of Bcl10 to its molecular partners in the NF-kB/Rel-activating machinery. 41 Bcl10 expression in MALT lymphoma correlates with NF-kB/Rel nuclear levels. 42 Another MALT lymphoma translocation, t(11;18)(q21;q21), produces API2-MALT1, by fusing the gene for the human caspase-like molecule MLT1 to the caspase inhibitor -encoding gene iap2; 43 such a fusion activates NF-kB/ Rel factors.…”

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confidence: 99%

NF-κB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors

et al. 2003

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The activity of NF-jB/Rel transcription factors can downmodulate apoptosis in normal and neoplastic cells of the hematologic and other compartments, contributing in maintaining neoplastic clone survival and impairing response to therapy. Alterations in nfjb or ijB genes are documented in some hematologic neoplasias, while in others dysfunction in NF-jB/Rel-activating signaling pathways can be recognized. The prosurvival properties of NF-jB/Rel appear to rely on the induced expression of molecules (caspase inhibitors, Bcl2 protein family members, etc.), which interfere with the apoptosis pathway. Constitutive NF-jB/Rel activity in some hematologic malignancies could be advantageous for neoplastic clone expansion by counteracting stress stimuli (consumption of growth factors and metabolites) and immune system-triggered apoptosis; it is furthermore likely to play a central role in determining resistance to therapy. Based on this evidence, NFjB/Rel-blocking approaches have been introduced in antineoplastic strategies. The identification of NF-jB/Rel target genes relevant for survival in specific neoplasias is required in order to address tailored therapies and avoid possible detrimental effects due to widespread NF-jB/Rel inhibition. Moreover, comparative analyses of normal hematopoietic progenitors and neoplastic cell sensitivities to inhibitors of NF-jB/Rel and their target genes will allow to evaluate the impact of these tools on normal bone marrow. Regulation of apoptosis by NF-jB/Rel factors NF-kB/Rel transcription factors are dimers of proteins (p50/p105 or NF-kB1, p52/p100 or NF-kB2, p65 or RelA, c-Rel and RelB) containing an approximately 300 amino-acid REL homology domain (RHD), which mediates protein dimerization and binding to DNA. 1 The RHD is also involved in interacting with the ankyrin repeats of IkB, a family of proteins coevolved with NF-kB/Rel. 1,2 NF-kB/Rel dimers are retained in the cytoplasm of several cell types by inhibitors of the IkB family. Growth factors, cytokines, hormones or other agents can induce, through the IKK (IkB-kinase) cascade or other kinases, 1,2 the phosphorylation and ubiquitin-mediated degradation of the IkB proteins, allowing the NF-kB/Rel dimers to reach the nucleus. 3 NF-kB/Rel activation is also induced by stress stimuli that provoke increases in the intracellular concentration of reactive oxygen species (ROS), imbalance in calcium ions fluxes and/or accumulation of unfolded proteins in the endoplasmic reticulum (RE). Such events trigger the activation of stress kinases and other modulators, which ultimately lead to IkB degradation. [1][2][3]

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“…Hitherto, studies on Bcl10 have mostly been carried out on various types of lymphomas (44). In such tumors, Bcl10 is phosphorylated by several PKs, including Ca 2+ -calmodulin-dependent PKⅡ, AKT1, p38-MAPK, IκB kinase and PKC (21,30). Recently Kuo et al (45) demonstrated that the suppression of Bcl10 by siRNA hindered the growth of 4 otherwise untreated HCC cell lines (i.e., C33A, CaSki, HeLa and SiHa) through the NF-κB-dependent regulation of cyclin D1.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that the enforced overexpression of wt Bcl10 protein weakly induces apoptosis and activates NF-κB in cells; yet, the expression of a Bcl10 mutant protein, in which the CARD domain is truncated, does not trigger apoptosis but activates NF-κB (26,28,29). Evidence to date suggests that the Bcl10 protein is involved in the autoproteolytic activation of pro-caspase-9 (28), in dissociating caspases from their inhibitors, cellular inhibitor of apoptosis proteins (cIAPs) (30), and in the formation of pro-apoptotic complexes with PKCζ at the NMs of HCC C4-I cells (20,31).…”

Section: Bcl10 Crucially Nucleates the Pro-apoptotic Complexes Comprimentioning

confidence: 99%

Bcl10 crucially nucleates the pro-apoptotic complexes comprising PDK1, PKCζ and caspase-3 at the nuclear envelope of etoposide-treated human cervical carcinoma C4-I cells

Chiarini

Liu

Armato

et al. 2015

International Journal of Molecular Medicine

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Abstract. Protein kinase (PK)Cζ signaling at various subcellular levels affects cell survival, differentiation, growth and/or apoptosis. However, the mechanisms modulating PKCζ activity at the nuclear membrane (NM) are not yet fully understood. Previously, we demonstrated that PKCζ interacts with the B-cell lymphoma 10 (Bcl10) protein at the NM of human cervical carcinoma (HCC) C4-I cells. In the present study, we aimed to further clarify the interactions between PKCζ, Bcl10 and other proteins co-immunoprecipitated from NMs isolated from untreated and etoposide (also known as VP-16; 2.0 µg/ml)-treated C4-I cells using biochemical and proteomics analyses. Aside from the Bcl10 protein, 3-phosphoinositide-dependent protein kinase-1 (PDK1) also co-immunoprecipitated with PKCζ from NMs of C4-I cells, indicating the assembly of a heterotrimeric complex, which increased with time in VP-16-exposed cells, as did the activity of PDK1-phosphorylated-PKCζ. In turn, PKCζ-phosphorylated-Bcl10 straddled an enlarged complex which comprised caspase-3. Subsequently, activity-enhanced caspase-3 cleaved and inactivated PKCζ. Finally, the suppression of Bcl10 using specific siRNA or lentiviral transduction prevented the increase in the PDK1•PKCζ association, the increase in the activity of PKCζ and caspase-3, as well as the caspase-3-mediated PKCζ proteolysis and inactivation from occurring at the NMs of the VP-16-exposed C4-I cells. Our observations provide evidence that Bcl10 acts as a pivotal pro-apoptotic protein which crucially nucleates complexes comprising PDK1, PKCζ and active caspase-3 at the NMs of VP-16-exposed C4-I cells. Hence, our data suggest that Bcl10 and PKCζ are potential therapeutic targets in the treatment of HCC. IntroductionThe disease with the second highest rate of mortality, for women, is human cervical carcinoma (HCC), which is prevalent in developing countries (1,2). The majority of HCCs derive from epithelial cells that have been persistently infected with high-risk oncogenic human papillomaviruses (HPVs), which express the E6 and E7 mRNAs, and proteins binding/neutralizing anti-oncogenic p53 and pRb. Furthermore, other co-factors, which have been less thoroughly studied, also promote HCC development (3,4). Notably, a small percentage (10%) of HCCs develops independently of a persistent high-risk oncogenic HPV infection (5). The complex molecular mechanisms responsible for the development of HCCs thus remain partially unclear, and this hinders the identification of predictive markers for the early detection of malignancy development and the discovery of novel, effective therapies.Proteomics and bioinformatics analysis have allowed researchers to identify differential protein expression patterns and the molecular mechanisms responsible for the development of HCC (6). A previous study identified a consensus of 66 proteins termed the 'central core of HCC protein expression̓ which was deduced from the proteomes of 6 HCC cell lines (not comprising the C4-I cell line); this differed from the proteomic profile...

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Interchangeable binding of Bcl10 to TRAF2 and cIAPs regulates apoptosis signaling

Cited by 23 publications

References 27 publications

IAPS : More than just inhibitors of apoptosis proteins

IAPS : More than just inhibitors of apoptosis proteins

NF-κB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors

Bcl10 crucially nucleates the pro-apoptotic complexes comprising PDK1, PKCζ and caspase-3 at the nuclear envelope of etoposide-treated human cervical carcinoma C4-I cells

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