The Experts below are selected from a list of 15255 Experts worldwide ranked by ideXlab platform
Martin Holcik - One of the best experts on this subject based on the ideXlab platform.
-
rna binding protein hur mediates cytoprotection through stimulation of XIAP translation
Oncogene, 2011Co-Authors: Danielle Durie, Stephen M. Lewis, Martin Holcik, Urszula Liwak, M Kisilewicz, Myriam GorospeAbstract:Expression of the intrinsic cellular caspase inhibitor XIAP is regulated primarily at the level of protein synthesis. The 5′ untranslated region harbours an Internal Ribosome Entry Site (IRES) motif that supports cap-independent translation of XIAP mRNA during conditions of cellular stress. In this study, we show that the RNA-binding protein HuR, which is known to orchestrate an antiapoptotic cellular program, stimulates translation of XIAP mRNA through XIAP IRES. We further show that HuR binds to XIAP IRES in vitro and in vivo, and stimulates recruitment of the XIAP mRNA into polysomes. Importantly, protection from the apoptosis-inducing agent etoposide by overexpression of HuR requires the presence of XIAP, suggesting that HuR-mediated cytoprotection is partially executed through enhanced XIAP translation. Our data suggest that XIAP belongs to the HuR-regulated RNA operon of antiapoptotic genes, which, along with Bcl-2, Mcl-1 and ProTα, contributes to the regulation of cell survival.
-
Subcellular Relocalization of a Trans-acting Factor Regulates XIAP IRES-dependent Translation
Molecular Biology of the Cell, 2007Co-Authors: Stephen M. Lewis, Sophie Bonnal, Stephan Vagner, Anne Veyrier, Nicoleta Hosszu Ungureanu, Martin HolcikAbstract:Translation of the X-linked inhibitor of apoptosis (XIAP) proceeds by internal ribosome entry site (IRES)-mediated initiation, a process that is physiologically important because XIAP expression is essential for cell survival under conditions of compromised cap-dependent translation, such as cellular stress. The regulation of internal initiation requires the interaction of IRES trans-acting factors (ITAFs) with the IRES element. We used RNA-affinity chromatography to identify XIAP ITAFs and isolated the heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1). We find that hnRNP A1 interacts with XIAP IRES RNA both in vitro and in vivo and that hnRNP A1 negatively regulates XIAP IRES activity. Moreover, XIAP IRES-dependent translation is significantly reduced when hnRNP A1 accumulates in the cytoplasm. Osmotic shock, a cellular stress that causes cytoplasmic accumulation of hnRNP A1, also leads to a decrease in XIAP levels that is abrogated by knockdown of hnRNP A1 expression. These results suggest that the subcellular localization of hnRNP A1 is an important determinant of its ability to negatively regulate XIAP IRES activity, suggesting that the subcellular distribution of ITAFs plays a critical role in regulating IRES-dependent translation. Our findings demonstrate that cytoplasmic hnRNP A1 is a negative regulator of XIAP IRES-dependent translation, indicating a novel function for the cytoplasmic form of this protein.
-
Translational Upregulation of the X-Linked Inhibitor of Apoptosis
Annals of the New York Academy of Sciences, 2003Co-Authors: Martin HolcikAbstract:The X-linked inhibitor of apoptosis protein (XIAP) is the most potent and best studied intrinsic regulator of programmed cell death. The critical role XIAP plays in the control of apoptosis is also reflected in the complex ways the activity of XIAP is regulated. In addition to regulating the function of the protein, the synthesis of XIAP is also selectively regulated. XIAP is translated by a cap-independent mechanism of translation initiation that is mediated by a unique internal ribosome entry site (IRES) sequence element located in its 5' untranslated region. This allows XIAP mRNA to be actively translated during conditions of cellular stress when the majority of cellular protein synthesis is inhibited. The IRES regulation of XIAP translation points to an important mechanism in the control and regulation of apoptosis.
-
the internal ribosome entry site mediated translation of antiapoptotic protein XIAP is modulated by the heterogeneous nuclear ribonucleoproteins c1 and c2
Molecular and Cellular Biology, 2003Co-Authors: Martin Holcik, Bruce W Gordon, Robert G KornelukAbstract:The X-chromosome-linked inhibitor of apoptosis, XIAP, is the most powerful and ubiquitous intrinsic inhibitor of apoptosis. We have shown previously that the translation of XIAP is controlled by a potent internal ribosome entry site (IRES) element. IRES-mediated translation of XIAP is increased in response to cellular stress, suggesting the critical role for IRES translation during cellular stress. Here, we demonstrate that heterogeneous nuclear ribonucleoproteins C1 and C2 (hnRNPC1 and -C2) are part of the RNP complex that forms on XIAP IRES. Furthermore, the cellular levels of hnRNPC1 and -C2 parallel the activity of XIAP IRES and the overexpression of hnRNPC1 and -C2 specifically enhanced translation of XIAP IRES, suggesting that hnRNPC1 and -C2 may modulate XIAP expression. Given the central role of XIAP in the regulation of apoptosis these results are important for our understanding of the control of apoptosis.
-
functional characterization of the x linked inhibitor of apoptosis XIAP internal ribosome entry site element role of la autoantigen in XIAP translation
Molecular and Cellular Biology, 2000Co-Authors: Martin Holcik, Robert G KornelukAbstract:X-linked inhibitor of apoptosis protein (XIAP) is a key regulator of programmed cell death triggered by various apoptotic triggers. Translation of XIAP is controlled by a 162-nucleotide (nt) internal ribosome entry site (IRES) element located in the 5′ untranslated region of XIAP mRNA. XIAP IRES mediates efficient translation of XIAP under physiological stress and enhances cell protection against serum deprivation and radiation-induced apoptosis. In the present report we describe the assembly of a sequence-specific RNA-protein complex consisting of at least four cytosolic proteins on the XIAP IRES element. We determine that the core binding sequence is approximately 28 nt long and is located 34 nt upstream of the initiation site. Moreover, we identify the La autoantigen as a protein that specifically binds XIAP IRES in vivo and in vitro. The biological relevance of this interaction is further demonstrated by the inhibition of XIAP IRES-mediated translation in the absence of functional La protein. The results suggest an important role for the La protein in the regulation of XIAP expression, possibly by facilitating ribosome recruitment to the XIAP IRES.
Xuejun Jiang - One of the best experts on this subject based on the ideXlab platform.
-
a dimeric smac diablo peptide directly relieves caspase 3 inhibition by XIAP dynamic and cooperative regulation of XIAP by smac diablo
Journal of Biological Chemistry, 2007Co-Authors: Zhonghua Gao, Yuan Tian, Junru Wang, Qian Yin, Xuejun JiangAbstract:Caspase activation, the executing event of apoptosis, is under deliberate regulation. IAP proteins inhibit caspase activity, whereas Smac/Diablo antagonizes IAP. XIAP, a ubiquitous IAP, can inhibit both caspase-9, the initiator caspase of the mitochondrial apoptotic pathway, and the downstream effector caspases, caspase-3 and caspase-7. Smac neutralizes XIAP inhibition of caspase-9 by competing for binding of the BIR3 domain of XIAP with caspase-9, whereas how Smac liberates effector caspases from XIAP inhibition is not clear. It is generally believed that binding of Smac with IAP generates a steric hindrance that prevents XIAP from inhibiting effector caspases, and therefore small molecule mimics of Smac are not able to reverse inhibition of the effector caspases. Surprisingly, we show here that binding of a dimeric Smac N-terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase-3 by XIAP. Further, we defined the dynamic and cooperative interaction of Smac with XIAP: binding of Smac with the BIR3 domain anchors the subsequent binding of Smac with the BIR2 domain, which in turn attenuates the caspase-3 inhibitory function of XIAP. We also show that XIAP homotrimerizes via its C-terminal Ring domain, making its inhibitory activity toward caspase-3 more susceptible to Smac.
-
A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo.
The Journal of biological chemistry, 2007Co-Authors: Zhonghua Gao, Yuan Tian, Junru Wang, Qian Yin, Xuejun JiangAbstract:Caspase activation, the executing event of apoptosis, is under deliberate regulation. IAP proteins inhibit caspase activity, whereas Smac/Diablo antagonizes IAP. XIAP, a ubiquitous IAP, can inhibit both caspase-9, the initiator caspase of the mitochondrial apoptotic pathway, and the downstream effector caspases, caspase-3 and caspase-7. Smac neutralizes XIAP inhibition of caspase-9 by competing for binding of the BIR3 domain of XIAP with caspase-9, whereas how Smac liberates effector caspases from XIAP inhibition is not clear. It is generally believed that binding of Smac with IAP generates a steric hindrance that prevents XIAP from inhibiting effector caspases, and therefore small molecule mimics of Smac are not able to reverse inhibition of the effector caspases. Surprisingly, we show here that binding of a dimeric Smac N-terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase-3 by XIAP. Further, we defined the dynamic and cooperative interaction of Smac with XIAP: binding of Smac with the BIR3 domain anchors the subsequent binding of Smac with the BIR2 domain, which in turn attenuates the caspase-3 inhibitory function of XIAP. We also show that XIAP homotrimerizes via its C-terminal Ring domain, making its inhibitory activity toward caspase-3 more susceptible to Smac.
Robert G Korneluk - One of the best experts on this subject based on the ideXlab platform.
-
Modulation of immune signalling by inhibitors of apoptosis.
Trends in immunology, 2012Co-Authors: Shawn T. Beug, Herman H. Cheung, Eric C. Lacasse, Robert G KornelukAbstract:The inhibitor of apoptosis (IAP) genes are critical regulators of multiple pathways that control cell death, proliferation, and differentiation. Several members of the IAP family regulate innate and adaptive immunity through modulation of signal transduction pathways, cytokine production, and cell survival. The regulation of immunity by the IAPs is primarily mediated through the ubiquitin ligase function of cellular IAP (cIAP)1, cIAP2, and X-linked IAP (XIAP), the targets of which impact nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signalling pathways. In addition, neuronal apoptosis inhibitory protein (NAIP), cIAP1, and cIAP2 modulate innate immune responses through control of the inflammasome complex. This review examines the role of mammalian IAPs in regulating immunity and describes the implications of a new class of pan-IAP antagonists for the treatment of immune disorders.
-
the internal ribosome entry site mediated translation of antiapoptotic protein XIAP is modulated by the heterogeneous nuclear ribonucleoproteins c1 and c2
Molecular and Cellular Biology, 2003Co-Authors: Martin Holcik, Bruce W Gordon, Robert G KornelukAbstract:The X-chromosome-linked inhibitor of apoptosis, XIAP, is the most powerful and ubiquitous intrinsic inhibitor of apoptosis. We have shown previously that the translation of XIAP is controlled by a potent internal ribosome entry site (IRES) element. IRES-mediated translation of XIAP is increased in response to cellular stress, suggesting the critical role for IRES translation during cellular stress. Here, we demonstrate that heterogeneous nuclear ribonucleoproteins C1 and C2 (hnRNPC1 and -C2) are part of the RNP complex that forms on XIAP IRES. Furthermore, the cellular levels of hnRNPC1 and -C2 parallel the activity of XIAP IRES and the overexpression of hnRNPC1 and -C2 specifically enhanced translation of XIAP IRES, suggesting that hnRNPC1 and -C2 may modulate XIAP expression. Given the central role of XIAP in the regulation of apoptosis these results are important for our understanding of the control of apoptosis.
-
functional characterization of the x linked inhibitor of apoptosis XIAP internal ribosome entry site element role of la autoantigen in XIAP translation
Molecular and Cellular Biology, 2000Co-Authors: Martin Holcik, Robert G KornelukAbstract:X-linked inhibitor of apoptosis protein (XIAP) is a key regulator of programmed cell death triggered by various apoptotic triggers. Translation of XIAP is controlled by a 162-nucleotide (nt) internal ribosome entry site (IRES) element located in the 5′ untranslated region of XIAP mRNA. XIAP IRES mediates efficient translation of XIAP under physiological stress and enhances cell protection against serum deprivation and radiation-induced apoptosis. In the present report we describe the assembly of a sequence-specific RNA-protein complex consisting of at least four cytosolic proteins on the XIAP IRES element. We determine that the core binding sequence is approximately 28 nt long and is located 34 nt upstream of the initiation site. Moreover, we identify the La autoantigen as a protein that specifically binds XIAP IRES in vivo and in vitro. The biological relevance of this interaction is further demonstrated by the inhibition of XIAP IRES-mediated translation in the absence of functional La protein. The results suggest an important role for the La protein in the regulation of XIAP expression, possibly by facilitating ribosome recruitment to the XIAP IRES.
-
a new internal ribosome entry site motif potentiates XIAP mediated cytoprotection
Nature Cell Biology, 1999Co-Authors: Martin Holcik, Charles Lefebvre, Chiaoli Yeh, Terry Chow, Robert G KornelukAbstract:rogrammed cell death (apoptosis) plays a critical part in regulating cell turnover during embryogenesis, metamorphosis, tissue homeostasis and viral infection1. Dysregulation of apoptosis occurs in such pathologies as cancer, autoimmunity, immunodeficiency and neurodegeneration. Proteins of the inhibitor-ofapoptosis (IAP) family are intrinsic cellular suppressors of apoptosis and are represented by highly conserved members found from insect viruses to mammals2‐4. The most potent mammalian IAP is the X-linked IAP, or XIAP5, whose mechanism of action involves direct inhibition of caspases 3 and 7, key proteases of the apoptotic cascade6. Cellular control of XIAP expression should be fundamental to a cell’s ability to modulate its responses to apoptotic stimuli. However, XIAP messenger RNA is expressed in most tissues and cells at fairly constant levels5, indicating that translational control of XIAP levels may be an important regulatory mechanism. Here we characterize the primary genomic structure and function of XIAP, and show that XIAP expression is controlled at the translational level, specifically through an internal ribosome-entry site (IRES). Several features of XIAP mRNA indicate that it may be translationally regulated, including an unusually long 5′ untranslated region (UTR) (>5.5 kilobases (kb) for murine and >1.6 kb for human XIAP transcripts) with predicted complex secondary structure and numerous potential translation start sites upstream of the authentic initiation codon. This UTR would be expected to present a significant obstacle to efficient translation by conventional ribosome scanning7. An alternative mechanism of translation initiation, mediated through the IRES, has been identified in picornaviruses and in a few cellular mRNAs8. Thus we tested whether the 5′ UTR of XIAP mRNA could be involved in translation initiation from reporter-based bicistronic mRNA transcripts encoding β-galactosidase and chloramphenicol aceytyltransferase (CAT) (for example, see ref. 9). (Translation of β-galactosidase is driven by the 5′ mRNA methylguanosine cap.) Both human and mouse XIAP 5′ UTRs directed translation of the second cistron (encoding CAT) at 150fold higher levels than those produced without the 5′ UTR or with the 5′ UTR in reverse orientation, suggesting the presence of an IRES (Fig. 1a). No activity was detected when using the identical DNA segments cloned into a promoterless construct, confirming P
Zhonghua Gao - One of the best experts on this subject based on the ideXlab platform.
-
a dimeric smac diablo peptide directly relieves caspase 3 inhibition by XIAP dynamic and cooperative regulation of XIAP by smac diablo
Journal of Biological Chemistry, 2007Co-Authors: Zhonghua Gao, Yuan Tian, Junru Wang, Qian Yin, Xuejun JiangAbstract:Caspase activation, the executing event of apoptosis, is under deliberate regulation. IAP proteins inhibit caspase activity, whereas Smac/Diablo antagonizes IAP. XIAP, a ubiquitous IAP, can inhibit both caspase-9, the initiator caspase of the mitochondrial apoptotic pathway, and the downstream effector caspases, caspase-3 and caspase-7. Smac neutralizes XIAP inhibition of caspase-9 by competing for binding of the BIR3 domain of XIAP with caspase-9, whereas how Smac liberates effector caspases from XIAP inhibition is not clear. It is generally believed that binding of Smac with IAP generates a steric hindrance that prevents XIAP from inhibiting effector caspases, and therefore small molecule mimics of Smac are not able to reverse inhibition of the effector caspases. Surprisingly, we show here that binding of a dimeric Smac N-terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase-3 by XIAP. Further, we defined the dynamic and cooperative interaction of Smac with XIAP: binding of Smac with the BIR3 domain anchors the subsequent binding of Smac with the BIR2 domain, which in turn attenuates the caspase-3 inhibitory function of XIAP. We also show that XIAP homotrimerizes via its C-terminal Ring domain, making its inhibitory activity toward caspase-3 more susceptible to Smac.
-
A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo.
The Journal of biological chemistry, 2007Co-Authors: Zhonghua Gao, Yuan Tian, Junru Wang, Qian Yin, Xuejun JiangAbstract:Caspase activation, the executing event of apoptosis, is under deliberate regulation. IAP proteins inhibit caspase activity, whereas Smac/Diablo antagonizes IAP. XIAP, a ubiquitous IAP, can inhibit both caspase-9, the initiator caspase of the mitochondrial apoptotic pathway, and the downstream effector caspases, caspase-3 and caspase-7. Smac neutralizes XIAP inhibition of caspase-9 by competing for binding of the BIR3 domain of XIAP with caspase-9, whereas how Smac liberates effector caspases from XIAP inhibition is not clear. It is generally believed that binding of Smac with IAP generates a steric hindrance that prevents XIAP from inhibiting effector caspases, and therefore small molecule mimics of Smac are not able to reverse inhibition of the effector caspases. Surprisingly, we show here that binding of a dimeric Smac N-terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase-3 by XIAP. Further, we defined the dynamic and cooperative interaction of Smac with XIAP: binding of Smac with the BIR3 domain anchors the subsequent binding of Smac with the BIR2 domain, which in turn attenuates the caspase-3 inhibitory function of XIAP. We also show that XIAP homotrimerizes via its C-terminal Ring domain, making its inhibitory activity toward caspase-3 more susceptible to Smac.
Yide Mei - One of the best experts on this subject based on the ideXlab platform.
-
XIAP inhibits autophagy via XIAP mdm2 p53 signalling
The EMBO Journal, 2013Co-Authors: Xing Huang, Yide MeiAbstract:The primary role of autophagy is adaption to starvation. However, increasing evidence suggests that autophagy inhibition also plays an important role in tumorigenesis. Upregulation of X-linked inhibitor of apoptosis (XIAP) has been associated to a variety of human cancers, yet the underlying mechanisms remain obscure. Here, we report that XIAP suppresses autophagy by exerting a previously unidentified ubiquitin E3 ligase activity towards Mdm2, which is a negative regulator of p53. XIAP controls serum starvation-induced autophagy downstream of the PI3K/Akt pathway. In mouse models, inhibition of autophagy by XIAP promotes tumorigenecity of HCT116 cells. XIAP-mediated autophagy inhibition is also largely validated in clinical tumour samples. These findings reveal a novel XIAP-Mdm2-p53 pathway that mediates the inhibition of autophagy, by which XIAP may contribute to tumorigenesis.
-
XIAP inhibits autophagy via XIAP‐Mdm2‐p53 signalling
The EMBO journal, 2013Co-Authors: Xing Huang, Yide MeiAbstract:The primary role of autophagy is adaption to starvation. However, increasing evidence suggests that autophagy inhibition also plays an important role in tumorigenesis. Upregulation of X-linked inhibitor of apoptosis (XIAP) has been associated to a variety of human cancers, yet the underlying mechanisms remain obscure. Here, we report that XIAP suppresses autophagy by exerting a previously unidentified ubiquitin E3 ligase activity towards Mdm2, which is a negative regulator of p53. XIAP controls serum starvation-induced autophagy downstream of the PI3K/Akt pathway. In mouse models, inhibition of autophagy by XIAP promotes tumorigenecity of HCT116 cells. XIAP-mediated autophagy inhibition is also largely validated in clinical tumour samples. These findings reveal a novel XIAP-Mdm2-p53 pathway that mediates the inhibition of autophagy, by which XIAP may contribute to tumorigenesis.