Posttranscriptional Downregulation of c-IAP2 by the Ubiquitin Protein Ligase c-IAP1 In Vivo

Conze, Dietrich B.; Albert, Lori; Ferrick, David A.; Goeddel, David V.; Yeh, Wen-Chen; Mak, Tak W.; Ashwell, Jonathan D.

doi:10.1128/mcb.25.8.3348-3356.2005

Cited by 170 publications

(193 citation statements)

References 48 publications

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“…20 Likewise, targeted gene disruption of cIAP1 and cIAP2 has not revealed any significant apoptotic phenotypes. 21,22 Although these results could be interpreted to indicate that IAPs do not play a major role for caspase regulation in mammals, a more likely alternative is that their physiological role is masked by functional redundancy. If relatively short-lived organisms such as fruit flies protect themselves against unwanted death using multiple caspase inhibitors (see below; Figure 1), 6,[8][9][10][11][12][13][14][15][23][24][25][26][27][28][29][30][31][32][33][34][35] it would come as a great surprise if mammals would employ fewer safeguards to control caspase activity.…”

Section: Brakes On Death: Caspase Inhibition By Inhibitor Of Apoptosimentioning

confidence: 86%

Regulation of apoptosis in Drosophila

2008

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Insects have made major contributions to understanding the regulation of cell death, dating back to the pioneering work of Lockshin and Williams on death of muscle cells during postembryonic development of Manduca. A physically smaller cousin of moths, the fruit fly Drosophila melanogaster, offers unique advantages for studying the regulation of cell death in response to different apoptotic stimuli in situ. Different signaling pathways converge in Drosophila to activate a common death program through transcriptional activation of reaper, hid and grim. Reaper-family proteins induce apoptosis by binding to and antagonizing inhibitor of apoptosis proteins (IAPs), which in turn inhibit caspases. This switch from life to death relies extensively on targeted degradation of cell death proteins by the ubiquitin-proteasome pathway. Drosophila IAP-1 (Diap1) functions as an E3-ubiquitin ligase to protect cells from unwanted death by promoting the degradation of the initiator caspase Dronc. However, in response to apoptotic signals, Reaper-family proteins are produced, which promote the auto-ubiquitination and degradation of Diap1, thereby removing the 'brakes on death' in cells that are doomed to die. More recently, several other ubiquitin pathway proteins were found to play important roles for caspase regulation, indicating that the control of cell survival and death relies extensively on targeted degradation by the ubiquitin-proteasome pathway.

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Section: Brakes On Death: Caspase Inhibition By Inhibitor Of Apoptosimentioning

confidence: 86%

Regulation of apoptosis in Drosophila

2008

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“…This lack of phenotype was most probably related to markedly elevated levels of c-IAP2 in c-IAP1-deficient mouse cells with redundancies in the functions of the two proteins. 14 Other potential explanations include the use of alternative pathways of differentiation when c-IAP1 is disrupted or the appearance of specific c-IAP1 functions in humans as compared to mice. Interaction networks emerging from large scale experiments demonstrate that HSP90 plays a central role in multiple pathways and cellular processes.…”

Section: Discussionmentioning

confidence: 99%

“…However, cells from c-IAP1À/À mice express markedly elevated levels of its highly homologous protein c-IAP2, suggesting that a redundancy in the function of the two proteins might take place. 14 Deletion of several other IAPs have demonstrated to lead to defaults in the development. XIAP deficiency delays development of the mammary gland 15 whereas that of BRUCE, a giant E3 ubiquitin ligase IAP, affects placenta development 16 and T-cell maturation.…”

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confidence: 99%

Interaction of heat-shock protein 90β isoform (HSP90β) with cellular inhibitor of apoptosis 1 (c-IAP1) is required for cell differentiation

et al. 2008

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Members of the inhibitor of apoptosis protein (IAP) family have demonstrated functions in cell death, cell signalling, cell migration and mitosis. Several of them are E3 enzymes in the ubiquitination of proteins that leads to their degradation by the proteosomal machinery. We previously reported that one of them, cellular inhibitor of apoptosis protein-1 (c-IAP1), migrated from the nucleus to the surface of the Golgi apparatus in cells undergoing differentiation. Here, we show that c-IAP1 is a client protein of the stress protein HSP90b. In three distinct cellular models, the two proteins interact and migrate from the nucleus to the cytoplasm along the differentiation process through a leptomycin B-sensitive pathway. Inhibition of HSP90 proteins by small chemical molecules and specific depletion of HSP90b isoform by siRNA both lead to auto-ubiquitination of c-IAP1 and its degradation by the proteasome machinery. This chaperone function of HSP90 towards c-IAP1 is specific of its b isoform as specific depletion of HSP90a does not affect c-IAP1 content. Chemical inhibition of HSP90 or siRNA-mediated depletion of HSP90b both inhibit cell differentiation, which can be reproduced by siRNA-mediated depletion of c-IAP1. Altogether, these results suggest that HSP90b prevents auto-ubiquitination and degradation of its client protein c-IAP1, whose depletion would be sufficient to inhibit cell differentiation. Members of the inhibitor of apoptosis protein (IAP) family were initially described as a series of natural inhibitors of cell death. Among the eight human proteins of this family, X-linked IAP (XIAP) demonstrated to be the bona fide caspase inhibitor 1 whereas the others demonstrated, for the most part, functions in cell signalling 2 and mitosis. 3 Several of these proteins harbour a Really Interesting New Gene (RING) domain at the carboxy terminus and function as an E3 enzyme in the cascade of ubiquitination that targets proteins to the ubiquitinproteasome degradation machinery. 4 One of these IAP with a RING domain is cellular IAP1 (c-IAP1) that was initially described as a signalling molecule. 2 Although c-IAP1 has subsequently been described as a direct inhibitor of caspases, this remains a controversial issue. 5,6 Due to its E3 function, c-IAP1 is responsible for the ubiquitination and subsequent degradation of the adaptor protein TNF receptor associated factor 2 7 and the serinethreonine apoptosis signal-regulating kinase 1 8 in the tumour necrosis factor alpha (TNFa) signalling pathway. In this TNFa pathway, c-IAP1 was reported also to interact with the serinethreonine kinases receptor interacting protein 2 and nuclear factor kappaB (NF-kB) essential modifier, upstream of NF-kB, 9 and to block caspase-8 activation, downstream of NF-kB. 10 Deletion experiments in Drosophila melanogaster have revealed other functions of IAPs in cell differentiation, 11 cell migration, 12 and immune response. 13 In mammals, c-IAP1-deficient mice develop normally. However, cells from c-IAP1À/À mice express markedly elevated levels ...

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“…9 Also, the protein turnover of cIAP2 is regulated by the ubiquitin ligase activity of cIAP1. 10 In contrast, cIAP1 levels are controlled at the level of protein synthesis. The 5 0 untranslated region (UTR) of cIAP1 contains an upstream open reading frame that reduces the basal translation of cIAP1.…”

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confidence: 99%

hnRNP A1 regulates UV-induced NF-κB signalling through destabilization of cIAP1 mRNA

et al. 2008

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cIAP1 is an important member of the inhibitor of apoptosis family of proteins and is involved in the regulation of the NF-jBsignalling pathway downstream of the TNF receptor. We report here that UV irradiation leads to downregulation of cIAP1 expression because of enhanced cIAP1 mRNA destabilization. An AU-rich element located within the 3 0 untranslated region of cIAP1 mRNA is sufficient to mediate cIAP1 mRNA instability. Furthermore, we have identified hnRNP A1 as a cIAP1 3 0 UTR-binding protein. hnRNP A1 is a primarily nuclear protein, but accumulates in the cytoplasm after exposure of cells to UV irradiation. Indeed, we find that hnRNP A1 enhances the destabilization of cIAP1 mRNA during UV irradiation. Moreover, siRNAmediated knockdown of hnRNP A1 restores cIAP1 levels and prevents UV irradiation-induced activation of the NF-jB signal transduction pathway, suggesting that hnRNP A1 is an essential post-transcriptional modulator of cIAP1 expression, and thus cIAP1 activity. The inhibitor of apoptosis (IAP) family of proteins are key regulators of programmed cell death. 1 The IAP family comprises eight distinct members that participate in diverse cellular processes including cell cycle, signal transduction, ubiquitylation, and caspase inhibition. 2 Although it was initially believed that all IAPs are capable of inhibiting distinct caspases, the recent data suggest that only XIAP is a bona fide caspase inhibitor. 3 cIAP1 and cIAP2 were identified through an interaction with the TNF-receptor complex proteins TRAF1 and TRAF2, which regulate NF-kB signalling through the TNF receptor. 4 The C-terminal RING finger domain of cIAP1 possesses an ubiquitin E3 ligase activity and may sensitize cells to apoptosis by direct ubiquitylation and removal of TRAF2 following activation of the TNF receptor, resulting in the inhibition of NF-kB pathways. 5 Indeed, cIAP1 degradation induced by Smac mimetics leads to activation of both the canonical and non-canonical NF-kB pathways, strengthening the importance of IAPs in the regulation of NF-kB signalling. [6][7][8] Although cIAP1 and cIAP2 perform similar functions within the cell, their expression is regulated differently. The expression of cIAP2 is controlled primarily at the level of transcription in an NF-kB-dependent manner. 9 Also, the protein turnover of cIAP2 is regulated by the ubiquitin ligase activity of cIAP1. 10 In contrast, cIAP1 levels are controlled at the level of protein synthesis. The 5 0 untranslated region (UTR) of cIAP1 contains an upstream open reading frame that reduces the basal translation of cIAP1. 11 The 5 0 UTR of cIAP1 also harbours an internal ribosome entry site (IRES) element that mediates translational induction of cIAP1 in response to stress. 12,13 This complex regulatory network reflects the distinct spatial and temporal requirement for cIAP1 and cIAP2 proteins in response to various physiological conditions.Here, we describe an additional regulatory mechanism that governs the expression of cIAP1. We find that following UV irradiation the levels...

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Posttranscriptional Downregulation of c-IAP2 by the Ubiquitin Protein Ligase c-IAP1 In Vivo

Cited by 170 publications

References 48 publications

Regulation of apoptosis in Drosophila

Regulation of apoptosis in Drosophila

Interaction of heat-shock protein 90β isoform (HSP90β) with cellular inhibitor of apoptosis 1 (c-IAP1) is required for cell differentiation

hnRNP A1 regulates UV-induced NF-κB signalling through destabilization of cIAP1 mRNA

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