cIAP1, cIAP2, and XIAP Act Cooperatively via Nonredundant Pathways to Regulate Genotoxic Stress–Induced Nuclear Factor-κB Activation

Jin, Hyung‐seung; Lee, Dong Hee; Kim, Dong Hwan U.; Chung, Ji Hye U.; Lee, Seul Ji U.; Lee, Tae

doi:10.1158/0008-5472.can-08-2256

Cited by 96 publications

(106 citation statements)

References 45 publications

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“…The fact that no additional increase in apoptosis susceptibility was seen when the XIAP knockdown fibroblasts were treated with the Smac/ Diablo mimetics (Figure 7; Figure E3) suggests that the enhanced apoptosis observed in cells treated with the Smac/ Diablo mimetics is attributable to inhibition of XIAP and that XIAP inhibition is sufficient to regulate the apoptosis susceptibility of these cells. Although there was no significant difference in the expression of cIAP1 and cIAP2 between normal and IPF lung fibroblasts, the relative expression of these IAPs did correlate with XIAP in the IPF fibroblasts, suggesting that they are similarly regulated and may have a cooperative function with XIAP (50). However, these studies also suggest that any contribution to apoptosis resistance mediated by cIAP1 or cIAP2 was dependent on the presence of functionally intact XIAP.…”

Section: Discussionmentioning

confidence: 65%

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (XIAP) has been suggested by prior studies showing that (1) XIAP is localized to fibroblastic foci in IPF tissue and (2) prostaglandin E 2 suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-b1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-b1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fasmediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.Keywords: myofibroblast; idiopathic pulmonary fibrosis; inhibitor of apoptosis; lung fibrosis; apoptosis Mesenchymal cells display a dynamic spectrum of phenotypes ranging between an undifferentiated state (fibroblast) and a differentiated state (myofibroblast) (1, 2). Although these effector cells are essential for the homeostatic reestablishment of normal architecture and function after tissue injury, the persistence of these cells is associated with fibrosis (3, 4). The resolution phase of normal wound repair coincides with the reduction of fibroblast numbers by apoptosis, but the triggers of apoptosis in normal wound repair and the mechanisms underlying the persistence of fibroblasts during fibrotic wound repair remain poorly understood (5, 6). The profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 have been found to promote resistance to apoptotic stimuli in fibroblasts, and the antifibrotic lipid mediator prostaglandin (PG)E 2 has been shown to increase the responsiveness of these cells to apoptotic stimuli, supporting a role for dysregulation of fibroblast apoptosis in the pathogenesis of fibrosis (7-12).Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology that is characterized by progressive alveolar fibrosis (13,14). The overall prognosis of patie...

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Section: Discussionmentioning

confidence: 65%

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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“…These observations suggest that NEMO monoubiquitination is critical for NEMO export and ATM has additional downstream role(s) independent of NEMO phosphorylation. Jin et al [68] recently found that cIAP1 is the K277/K309-specific NEMO ubiquitin ligase involved in the genotoxic stress signaling. In consonance with the hypothesis that ATM mediates additional downstream function(s), a small fraction of activated ATM is exported to the cytoplasm of HEK293 cells in a NEMO-dependent manner, and associates with IKΚβ along with ELKS (a protein rich in glutamic acid, leucine, lysine and serine) [54].…”

Section: Nuclear Export Of Nemo and Atmmentioning

confidence: 99%

“…In addition to identifying cIAP1 as the ligase responsible for NEMO monoubiquitination, Jin et al [68] further found that TAK1 is required for NF-κB activation by VP16 and CPT, and that cIAP1 is also required for TAK1 activation by these agents. Thus, the authors placed cIAP1-mediated NEMO monoubiquitination upstream of TAK1 activation.…”

Section: Atm-dependent Ikk Activation In the Cytoplasmmentioning

confidence: 99%

“…Although some controversies exist in the above studies [15,68,70], several consensus points may be drawn regarding the mechanism of NF-κB activation by CPT, VP16 and IR (Figure 2). First, NEMO has a unique upstream role entirely independent of its role as a regulatory component of the canonical IKK complex.…”

Section: Atm-dependent Ikk Activation In the Cytoplasmmentioning

confidence: 99%

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Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

2010

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A large body of literature describes elaborate NF-κB signaling networks induced by inflammatory and immune signals. Decades of research has revealed that transcriptionally functional NF-κB dimers are activated by two major pathways, canonical and non-canonical. Both pathways involve the release of NF-κB dimers from inactive cytoplasmic complexes to cause their nuclear translocation to modulate gene expression programs and biological responses. NF-κB is also responsive to genotoxic agents; however, signal communication networks that are initiated in the nucleus following DNA damage induction are less defined. Evidence in the literature supports the presence of such signaling pathways induced by multiple distinct genotoxic agents, resulting in the activation of cytoplasmic IKK complex. An example is a pathway that involves the DNA damage-responsive kinase ataxia telangiectasia mutated (ATM) and a series of post-translational modifications of NF-κB essential modulator (NEMO) in the nucleus of a genotoxinexposed cell. Recent evidence also suggests that this nuclear-initiated NF-κB signaling pathway plays significant physiological and pathological roles, particularly in lymphocyte development and human cancer progression. This review will summarize these new developments, while identifying significant unanswered questions and providing new hypotheses that may be addressed in future studies.

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“…PIDD has been shown to translocate to the nucleus in response to genotoxic stress, and either PIDD or RIP1 depletion abolishes DNA damage-induced NF-B activation and NEMO sumoylation (11). Once sumoylated, NEMO is phosphorylated by ATM and monoubiquitinated potentially by the inhibitor of apoptosis protein cIAP1 in the nucleus (9,12,27). These events trigger the translocation of ATM and NEMO into the cytosol (27); however, the mechanism by which NEMO monoubiquitination leads to IKK activation is unknown.…”

mentioning

confidence: 99%

A Cytosolic ATM/NEMO/RIP1 Complex Recruits TAK1 To Mediate the NF-κB and p38 Mitogen-Activated Protein Kinase (MAPK)/MAPK-Activated Protein 2 Responses to DNA Damage

Yang

Xia

Hermance

et al. 2011

Molecular and Cellular Biology

124

100

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In multiple tumor types, activation of the transcription factor NF-B increases the resistance of tumor cells to anticancer therapies and contributes to tumor progression. Genotoxic stress induced by chemotherapy or radiation therapy triggers the ATM-dependent translocation of NF-B essential modifier (NEMO), also designated I B kinase ␥ (IKK␥), from the nucleus to the cytosol, resulting in I B kinase activation by mechanisms not yet fully understood. RIP1 has been implicated in this response and found to be modified in cells with damaged DNA; however, the nature of the RIP1 modification and its precise role in the pathway remain unclear. Here, we show that DNA damage stimulates the formation of a cytosolic complex containing ATM, NEMO (IKK␥), RIP1, and TAK1. We find that RIP1 is modified by SUMO-1 and ubiquitin in response to DNA damage and demonstrate that modified RIP1 is required for NF-B activation and tumor cell survival. We show that ATM activates TAK1 in a manner dependent on RIP1 and NEMO. We also reveal TAK1 as a central mediator of the alternative DNA damage response pathway mediated by the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 (MAPKAP-2) kinases. These findings have translational implications and reveal RIP1 and TAK1 as potential therapeutic targets in chemoresistance.The DNA damage response activates cell cycle checkpoint and survival pathways that function to prevent DNA replication until damaged DNA is repaired. These pathways include the well-characterized ATM (ataxia telangiectasia mutated)/ CHK2 and ATR (ataxia telangiectasia and Rad-3 related)/ CHK1 pathways and the more recently identified ATM/ ATR/p38 mitogen-activated protein kinase (MAPK)/MAPKactivated protein 2 (MAPKAP-2; hereinafter called MK2) checkpoint that is active in p53-deficient tumor cells (15,19). The transcription factor NF-B regulates apoptosis induced by genotoxic stress and is an attractive therapeutic target in tumor cells whose response to DNA-damaging agents is impaired due to compromised p53 function. Moreover, constitutive NF-B activity is a hallmark of several cancers, and mutations in NF-B pathway components have been associated with the activated B cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL), breast cancer, and multiple myeloma (3, 6). Thus, the inclusion of NF-B inhibitors in cancer therapy could have antioncogenic activities as well as augment the tumor chemotherapeutic response.NF-B is normally held in the cytoplasm in an inactive form bound to inhibitor proteins, such as I B␣. Diverse stimuli, such as infection, proinflammatory cytokine production, or treatment with agents that induce DNA damage elicit NF-B-mediated transcriptional activity by activating the cytosolic I B kinase (IKK) complex, consisting of IKK␣ and IKK␤ and a regulatory subunit designated IKK␥ or NF-B essential modifier (NEMO) (hereinafter referred to as NEMO). IKK activation results in I B␣ phosphorylation, ubiquitination, and subsequent degradation. The NF-B (p65/p50) heterodimer is then free to en...

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cIAP1, cIAP2, and XIAP Act Cooperatively via Nonredundant Pathways to Regulate Genotoxic Stress–Induced Nuclear Factor-κB Activation

Cited by 96 publications

References 45 publications

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

A Cytosolic ATM/NEMO/RIP1 Complex Recruits TAK1 To Mediate the NF-κB and p38 Mitogen-Activated Protein Kinase (MAPK)/MAPK-Activated Protein 2 Responses to DNA Damage

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