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Translation inhibitors and their unique biological properties
European Journal of Pharmacology 676 (2012) 1–5
Contents lists available at SciVerse ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Perspective
Translation inhibitors and their unique biological properties Takao Kataoka ⁎ Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
a r t i c l e
i n f o
Article history: Received 7 September 2011 Accepted 28 November 2011 Available online 7 December 2011 Keywords: Apoptosis Ectodomain shedding Glutarimide Ribotoxic stress response TNF-α Translation Triene-ansamycin
a b s t r a c t In eukaryotes, many translation inhibitors have been widely used as bioprobes to evaluate the contribution of translation to signaling pathways and cellular functions. Several types of translation inhibitors are also known to trigger the activation of the mitogen-activated protein kinase superfamily in an intracellular mechanism called ribotoxic stress response. This perspective focuses on the biological properties of recently identified translation inhibitors that trigger ribotoxic stress response, particularly glutarimides as well as trieneansamycins. © 2011 Elsevier B.V. All rights reserved.
1. Introduction
2. NF-κB and apoptosis signaling pathways
Translation is the fundamental process of decoding an mRNA sequence into the amino acids of a protein. It is divided into three stages: initiation, elongation, and termination. The elongation process proceeds through three main steps: binding of aminoacyl tRNA to the ribosome A-site, peptide bond formation by transferring a nascent peptide in the P-site peptidyl tRNA to the A-site aminoacyl tRNA, and translocation of the P-site deacylated tRNA to the E-site and the A-site peptidyl tRNA to the P-site, which enables the next aminoacyl tRNA to enter the A-site. In eukaryotes, many translation inhibitors, such as cycloheximide, are known to block the elongation steps and have been widely used as bioprobes to evaluate the contribution of translation to signaling pathways and cellular functions (SchneiderPoetsch et al., 2010a). In addition, several types of translation inhibitors are able to trigger the activation of the mitogen-activated protein (MAP) kinase superfamily in an intracellular mechanism called ribotoxic stress response (Iordanov et al., 1997; Shifrin and Anderson, 1999; Sidhu and Omiecinski, 1998). This perspective focuses on recently identified translation inhibitors that trigger ribotoxic stress response and their unique biological activities in relation to tumor necrosis factor (TNF)-α-dependent signaling pathways leading to nuclear factor-κB (NF-κB) activation and apoptosis (Fig. 1).
Pro-inflammatory cytokines, such as TNF-α and interleukin (IL)-1, mainly induce the activation of the NF-κB signaling pathway, leading to the expression of a variety of genes essential for inflammation and other cellular functions. TNF receptor 1 (TNF-R1) and IL-1 receptor possess different cytoplasmic domains termed as the death domain and the Toll-IL-1 receptor domain, respectively, and trigger distinct signaling pathways by recruiting different sets of adaptor proteins (Bhoj and Chen, 2009; Hayden and Ghosh, 2008). However, these bifurcated signaling pathways converge to induce inhibitor of κB (IκB) kinase as the common signaling molecule. Phosphorylated IκB is subsequently ubiquitinated and hydrolyzed by 26S proteasome, leading to the liberation of NF-κB dimers from a cytosolic inactive complex pre-associating with IκB and their translocation to the nucleus where they activate the transcription of various target genes (Karin and Greten, 2005). Many types of natural and synthetic compounds have been identified to block the NF-κB signaling pathway induced by pro-inflammatory cytokines (Kataoka, 2009). In the apoptosis signaling pathway, death receptors, such as TNF-R1 and Fas, recruit the adaptor protein Fas-associated death domain (FADD) and the initiator procaspase-8 to their death domains and trigger the auto-activation of procaspase-8 into its fully active form that induces apoptosis by cleaving various substrates, such as effector procaspases (Danial and Korsmeyer, 2004). However, TNF-R1 and even Fas do not always cause apoptosis, mainly due to the expression of endogenous anti-apoptotic proteins, such as the caspase-8 modulator cellular FLICEinhibitory protein (c-FLIP). c-FLIP is capable of preventing the death-receptor-induced apoptosis via the interaction of FADD and procaspase-8 and is regulated by various transcription factors,
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T. Kataoka / European Journal of Pharmacology 676 (2012) 1–5
Fig. 1. Translation inhibitors and their mechanisms of actions on TNF-α-dependent signaling pathways. TNF-α induces NF-κB activation and upregulates c-FLIP expression, which blocks caspase-8 activation. Translation inhibitors prevent c-FLIP upregulation and thus sensitize many types of cells to TNF-α-induced apoptosis. TACE mediates the ectodomain shedding by converting membrane-anchored substrates, such as TNF-α and TNF-R1, into their soluble forms. Glutarimides, triene-ansamycins, anisomycin, and deoxynivalenol (gray box), but neither puromycin nor emetine, are able to induce ribotoxic stress response, leading to the activation of protein kinases. The MAP kinase superfamily members regulate the TACE-mediated ectodomain shedding and the apoptosis signaling pathway.
including NF-κB (Budd et al., 2006). It is well characterized that such translation inhibitors as cycloheximide diminish constitutive and NFκB-inducible c-FLIP expression and allow the activation of procaspase8 during death-receptor-mediated apoptosis (Kataoka, 2005). 3. TNF-α-converting enzyme (TACE) and ectodomain shedding TNF-α-converting enzyme (TACE), also referred to as a disintegrin and metalloproteinase 17, is a cell-surface metalloproteinase required
for the ectodomain shedding of many membrane-anchored proteins, such as cytokines (e.g., TNF-α) and receptors (e.g., TNF-R1 and TNF-R2) (Seals and Courtneidge, 2003). TACE plays a bifunctional role in the TNF-α signaling pathway in that the TACE-mediated ectodomain shedding generates soluble TNF-α as pro-inflammatory agonists and conversely downregulates cellsurface levels of TNF receptors, accompanied by the augmentation of soluble TNF receptors acting as anti-inflammatory antagonists (Scheller et al., 2011).
T. Kataoka / European Journal of Pharmacology 676 (2012) 1–5
TACE is ubiquitously expressed in various cell types and converted into its active form by the removal of its prodomain by furin proteinase in the Golgi compartment (Scheller et al., 2011). TACE activity is specifically regulated by an extracellular protein termed as the tissue inhibitor of metalloproteinase-3 (TIMP3). TIMP3 expression is upregulated by Jun proteins at the transcription level and controls the TACE-mediated TNF-α shedding during epidermal inflammation (Guinea-Viniegra et al., 2009). In response to various stimuli, extracellular signal-regulated kinase (ERK) and p38 MAP kinase phosphorylate the cytoplasmic domain of TACE at threonine 735 and thereby regulate the TACE-mediated ectodomain shedding (Díaz-Rodríguez et al., 2002; Liu et al., 2009; Soond et al., 2005; Xu and Derynck, 2010). In addition, the accessibility of the TACE catalytic site is regulated rapidly and reversibly by a mechanism that requires the transmembrane domain but not the cytoplasmic domain without depending on the prodomain removal (Le Gall et al., 2010). 4. Glutarimides and their biological properties Glutarimide antibiotics, such as cycloheximide, generally inhibit translation elongation by interfering with the translocation step. In a recently reported detailed mechanism, cycloheximide binds in the ribosomal E-site and stalls translocation by skewing the binding of deacylated tRNA to the E-site (Schneider-Poetsch et al., 2010b). As the most prominent translation inhibitor, cycloheximide has been widely used to sensitize many types of cells to the death-receptorinduced apoptosis (Kataoka, 2005). Cycloheximide is also known to cause rapid apoptosis in some cell types, including neutrophils, macrophages, and leukemia cell lines (Croons et al., 2007; Martin et al., 1990; Tang et al., 1999; Tsuchida et al., 1995). In human leukemia Jurkat cells, cycloheximide was shown to induce apoptosis via an FADD-dependent mechanism (Tang et al., 1999). In animal models, cycloheximide causes rapid induction of apoptosis in hepatocytes. This increases the mRNA levels of various genes for transcription factors as well as those related to apoptosis, ER stress, and inflammation (Ito et al., 2006). Acetoxycycloheximide, an acetoxyl analogue of cycloheximide, was found to induce apoptosis much more strongly than cycloheximide in Jurkat cells (Kadohara et al., 2005). In contrast to cycloheximide, acetoxycycloheximide dramatically induces the activation of ERK, c-Jun N-terminal kinase (JNK), and p38 MAP kinase (Kadohara et al., 2005). The JNK pathway plays an essential role in the regulation of apoptosis in response to various stresses and is required for the mitochondrial release of cytochrome c (Davis, 2000). JNK activation was found to mediate cytochrome c release during acetoxycycloheximideinduced apoptosis (Kadohara et al., 2005). As cycloheximide is known to induce MAP kinase activation at least to some extent (Croons et al., 2007; Iordanov et al., 1997; Kadohara et al., 2005; Sidhu and Omiecinski, 1998), it seems possible that MAP kinase signaling pathways are required for the cycloheximide-induced apoptosis. As the upstream transducers, double-stranded RNA-dependent protein kinase and hematopoietic cell kinase were identified to contribute to the activation of MAP kinase signaling pathways in response to trichothecene mycotoxins (e.g., deoxynivalenol) that interfere with the peptidyl transferase reaction (Pestka, 2010). Active caspase-8 cleaves the BH3-only protein Bid to generate its active form. Truncated Bid is translocated to mitochondria and initiates the mitochondrial release of cytochrome c into the cytosol, where cytochrome c, in turn, collaborates with adaptor protein Apaf-1 to activate initiator procaspase-9 (Danial and Korsmeyer, 2004). We recently found that Jurkat cells deficient in procaspase8 manifested inefficient mitochondrial release of pro-apoptotic proteins in response to acetoxycycloheximide; however, this was rescued by the reconstitution with catalytically inactive procaspase8 (Kadohara et al., 2009). These data supported the hypothesis that procaspase-8 mediates the mitochondrial release of pro-apoptotic
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proteins in a manner independent of its proteolytic activity during the acetoxycycloheximide-induced apoptosis. We also found that a portion of procaspase-8 was localized to mitochondria before and after exposure to acetoxycycloheximide (Kadohara et al., 2009). This is in agreement with the finding that cardiolipin anchors caspase8 at the contact sites between the inner and outer mitochondrial membranes (Gonzalvez et al., 2008). The molecular mechanism underlying the mediation of mitochondrial apoptosis signals during the acetoxycycloheximide-induced apoptosis by procaspase-8 remains to be clarified. Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface glycoprotein and its expression is drastically induced in an NF-κBdependent manner. In the course of screening for compounds that block the NF-κB signaling pathway, acetoxycycloheximide was initially identified to inhibit much more strongly ICAM-1 expression induced by TNF-α than that induced by IL-1 (Sugimoto et al., 2000). As the mechanism responsible for this selective inhibition, acetoxycycloheximide and, to a lesser extent, cycloheximide induced the ectodomain shedding of TNF-R1 by TACE via the activation of ERK and p38 MAP kinase, diminishing both apoptosis and NF-κB signaling pathways in response to TNF-α (Ogura et al., 2008a; Ogura et al., 2008b). Thus, translation inhibitors do not necessarily confer cell susceptibility to the TNF-α-induced apoptosis and in some cases, the combined treatment with TACE inhibitors or ERK and p38 MAP kinase inhibitors may be effective to promote the TNF-α-induced apoptosis. 5. Triene-ansamycins and their biological properties Ansamycins possess an aromatic moiety bridged by an aliphatic chain. They are classified into naphthalenoid ansamycins that generally inhibit RNA polymerase (e.g., rifamycin) and benzenoid ansamycins that exhibit more diverse functions (e.g., geldanamycin and herbimycin, which are Hsp90 inhibitors). The triene-ansamycin group of compounds belongs to benzenoid ansamycins and is characterized by the presence of a triene structure in the aliphatic chain. This group comprises various compounds, including mycotrienins (also termed as ansatrienins), trienomycins, and cytotrienins. The triene-ansamycin compounds were shown to exert various biological activities, such as antitumor activity, as well as the inhibition of phagocytosis, osteoclastic bone resorption, c-Src protein kinase, EGF receptor signaling, farnesyltransferase, NO production, and ERstress-induced X box-binding protein 1 (XBP1) activation (Feuerbach et al., 1995; Hara et al., 2000; Hosokawa et al., 1999; Kakeya et al., 1997; Kawamura et al., 2008; Kim et al., 2002; Magae et al., 1994; Sugita et al., 1982; Tashiro et al., 2007). Cytotrienin A has the common structural motifs of the trieneansamycin family plus an unusual aminocyclopropane carboxylic acid chain. Cytotrienin A was identified as an inducer of apoptosis in human leukemia HL-60 cells (Kakeya et al., 1997). Cytotrienin A induces the activation of protein kinases, including JNK, p38 MAP kinase, and p36 myelin basic protein, and the activation of these protein kinases is responsible for the induction of apoptosis (Kakeya et al., 1998; Watabe et al., 2000). Recently, cytotrienin A was shown to inhibit cellular protein synthesis (Lindqvist et al., 2010; Yamada et al., 2011a; Yamamoto et al., 2011). In translocation elongation, cytotrienin A interferes with the function of eukaryotic elongation factor 1A that delivers aminoacyl tRNA to the A-site of the ribosome (Lindqvist et al., 2010). Other triene-ansamycin family members, including mycotrienins, were found to inhibit cellular or cell-free protein synthesis (Yamada et al., 2011b; Yamamoto et al., 2011). These findings clearly indicate that the triene-ansamycin family is a novel class of translation inhibitors. XBP1 is a transcription factor that upregulates molecular chaperons to diminish the accumulation of unfolded proteins during ER stress. Inositol-requiring enzyme-1α is an endonuclease localized on the ER membrane and mediates the splicing of the precursor form
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of XBP1 mRNA to its active form. The translation inhibitor puromycin promotes premature peptide chain termination and releases incomplete nascent peptides from the ribosome (Yanagitani et al., 2011). Puromycin induces the accumulation of unfolded proteins, thereby promoting XBP1 mRNA splicing (Croons et al., 2008; Yamamoto et al., 2011). By contrast, cycloheximide does not induce the release of peptide chains from the ribosome and stabilizes polysomes (Schneider-Poetsch et al., 2010b). The triene-ansamycin compounds, including trierixin and quinotrierixin, were identified to inhibit ERstress-induced XBP1 activation (Kawamura et al., 2008; Tashiro et al., 2007). This is ascribed largely to the direct inhibition of translation in a manner similar to cycloheximide (Yamamoto et al., 2011). We have recently shown that mycotrienin II and cytotrienin A inhibit more strongly the cell-surface ICAM-1 expression induced by TNF-α than the expression induced by IL-1α (Yamada et al., 2011a; Yamada et al., 2011b). Acetoxycycloheximide and anisomycin, but neither puromycin nor emetine, inhibited the TNF-α-induced ICAM1 expression at lower concentrations than the IL-1-induced ICAM-1 expression (Yamada et al., 2011a). Cytotrienin A was found to induce the ectodomain shedding of TNF-R1 via the activation of ERK and p38 MAP kinase (Yamada et al., 2011a). This is in agreement with previous studies that cytotrienin A induces the activation of MAP kinase superfamily (Kakeya et al., 1998; Watabe et al., 2000), Thus, the triene-ansamycin family members are translation inhibitors that strongly induce ribotoxic stress response. 6. Conclusions and perspectives Translation inhibitors are highly useful bioprobes to analyze the contribution of translation to complex cellular responses and signaling pathways. Several types of translation inhibitors have been often used as strong inducers to trigger the activation of the MAP kinase superfamily. Recent studies by us and other groups have disclosed novel types of translation inhibitors that induce ribotoxic stress response, such as acetoxycycloheximide and the trieneansamycin family compounds. However, the detailed molecular mechanisms by which these translation inhibitors induce the activation of protein kinases and subsequently elicit various intracellular responses have been poorly characterized. The elucidation of those molecular mechanisms is expected to contribute to the discovery of unknown signaling pathways and cellular functions as well as the development of potential lead compounds for anti-cancer and antiinflammatory drugs. Acknowledgments This work was supported by a Grant-in-Aid for Scientific Research (KAKENHI) from Japan Society for the Promotion of Science (JSPS). References Bhoj, V.G., Chen, Z.J., 2009. Ubiquitylation in innate and adaptive immunity. Nature 458, 430–437. Budd, R.C., Yeh, W.C., Tschopp, J., 2006. cFLIP regulation of lymphocyte activation and development. Nat. Rev. Immunol. 6, 196–204. Croons, V., Martinet, W., Herman, A.G., Timmermans, J.P., De Meyer, G.R., 2007. Selective clearance of macrophages in atherosclerotic plaques by the protein synthesis inhibitor cycloheximide. J. Pharmacol. Exp. Ther. 320, 986–993. Croons, V., Martinet, W., Herman, A.G., De Meyer, G.R., 2008. Different effect of the protein synthesis inhibitors puromycin and cycloheximide on vascular smooth muscle cell viability. J. Pharmacol. Exp. Ther. 325, 824–832. Danial, N.N., Korsmeyer, S.J., 2004. Cell death: critical control points. Cell 116, 205–219. Davis, R.J., 2000. Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252. Díaz-Rodríguez, E., Montero, J.C., Esparís-Ogando, A., Yuste, L., Pandiella, A., 2002. Extracellular signal-regulated kinase phosphorylates tumor necrosis factor αconverting enzyme at threonine 735: a potential role in regulated shedding. Mol. Biol. Cell 13, 2031–2044. Feuerbach, D., Waelchli, R., Fehr, T., Feyen, J.H., 1995. Mycotrienins. A new class of potent inhibitors of osteoclastic bone resorption. J. Biol. Chem. 270, 25949–25955.
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Xu, P., Derynck, R., 2010. Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol. Cell 37, 551–566. Yamada, Y., Taketani, S., Osada, H., Kataoka, T., 2011a. Cytotrienin A, a translation inhibitor that induces ectodomain shedding of TNF receptor 1 via activation of ERK and p38 MAP kinase. Eur. J. Pharmacol. 667, 113–119. Yamada, Y., Tashiro, E., Taketani, S., Imoto, M., Kataoka, T., 2011b. Mycotrienin II, a translation inhibitor that prevents ICAM-1 expression induced by proinflammatory cytokines. J. Antibiot. 64, 361–366. Yamamoto, K., Tashiro, E., Imoto, M., 2011. Quinotrierixin inhibited ER stress-induced XBP1 mRNA splicing through inhibition of protein synthesis. Biosci. Biotechnol. Biochem. 75, 284–288. Yanagitani, K., Kimata, Y., Kadokura, H., Kohno, K., 2011. Translational pausing ensures membrane targeting and cytoplasmic splicing of XBP1u mRNA. Science 331, 586–589.
Contents lists available at SciVerse ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Perspective
Translation inhibitors and their unique biological properties Takao Kataoka ⁎ Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
a r t i c l e
i n f o
Article history: Received 7 September 2011 Accepted 28 November 2011 Available online 7 December 2011 Keywords: Apoptosis Ectodomain shedding Glutarimide Ribotoxic stress response TNF-α Translation Triene-ansamycin
a b s t r a c t In eukaryotes, many translation inhibitors have been widely used as bioprobes to evaluate the contribution of translation to signaling pathways and cellular functions. Several types of translation inhibitors are also known to trigger the activation of the mitogen-activated protein kinase superfamily in an intracellular mechanism called ribotoxic stress response. This perspective focuses on the biological properties of recently identified translation inhibitors that trigger ribotoxic stress response, particularly glutarimides as well as trieneansamycins. © 2011 Elsevier B.V. All rights reserved.
1. Introduction
2. NF-κB and apoptosis signaling pathways
Translation is the fundamental process of decoding an mRNA sequence into the amino acids of a protein. It is divided into three stages: initiation, elongation, and termination. The elongation process proceeds through three main steps: binding of aminoacyl tRNA to the ribosome A-site, peptide bond formation by transferring a nascent peptide in the P-site peptidyl tRNA to the A-site aminoacyl tRNA, and translocation of the P-site deacylated tRNA to the E-site and the A-site peptidyl tRNA to the P-site, which enables the next aminoacyl tRNA to enter the A-site. In eukaryotes, many translation inhibitors, such as cycloheximide, are known to block the elongation steps and have been widely used as bioprobes to evaluate the contribution of translation to signaling pathways and cellular functions (SchneiderPoetsch et al., 2010a). In addition, several types of translation inhibitors are able to trigger the activation of the mitogen-activated protein (MAP) kinase superfamily in an intracellular mechanism called ribotoxic stress response (Iordanov et al., 1997; Shifrin and Anderson, 1999; Sidhu and Omiecinski, 1998). This perspective focuses on recently identified translation inhibitors that trigger ribotoxic stress response and their unique biological activities in relation to tumor necrosis factor (TNF)-α-dependent signaling pathways leading to nuclear factor-κB (NF-κB) activation and apoptosis (Fig. 1).
Pro-inflammatory cytokines, such as TNF-α and interleukin (IL)-1, mainly induce the activation of the NF-κB signaling pathway, leading to the expression of a variety of genes essential for inflammation and other cellular functions. TNF receptor 1 (TNF-R1) and IL-1 receptor possess different cytoplasmic domains termed as the death domain and the Toll-IL-1 receptor domain, respectively, and trigger distinct signaling pathways by recruiting different sets of adaptor proteins (Bhoj and Chen, 2009; Hayden and Ghosh, 2008). However, these bifurcated signaling pathways converge to induce inhibitor of κB (IκB) kinase as the common signaling molecule. Phosphorylated IκB is subsequently ubiquitinated and hydrolyzed by 26S proteasome, leading to the liberation of NF-κB dimers from a cytosolic inactive complex pre-associating with IκB and their translocation to the nucleus where they activate the transcription of various target genes (Karin and Greten, 2005). Many types of natural and synthetic compounds have been identified to block the NF-κB signaling pathway induced by pro-inflammatory cytokines (Kataoka, 2009). In the apoptosis signaling pathway, death receptors, such as TNF-R1 and Fas, recruit the adaptor protein Fas-associated death domain (FADD) and the initiator procaspase-8 to their death domains and trigger the auto-activation of procaspase-8 into its fully active form that induces apoptosis by cleaving various substrates, such as effector procaspases (Danial and Korsmeyer, 2004). However, TNF-R1 and even Fas do not always cause apoptosis, mainly due to the expression of endogenous anti-apoptotic proteins, such as the caspase-8 modulator cellular FLICEinhibitory protein (c-FLIP). c-FLIP is capable of preventing the death-receptor-induced apoptosis via the interaction of FADD and procaspase-8 and is regulated by various transcription factors,
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Fig. 1. Translation inhibitors and their mechanisms of actions on TNF-α-dependent signaling pathways. TNF-α induces NF-κB activation and upregulates c-FLIP expression, which blocks caspase-8 activation. Translation inhibitors prevent c-FLIP upregulation and thus sensitize many types of cells to TNF-α-induced apoptosis. TACE mediates the ectodomain shedding by converting membrane-anchored substrates, such as TNF-α and TNF-R1, into their soluble forms. Glutarimides, triene-ansamycins, anisomycin, and deoxynivalenol (gray box), but neither puromycin nor emetine, are able to induce ribotoxic stress response, leading to the activation of protein kinases. The MAP kinase superfamily members regulate the TACE-mediated ectodomain shedding and the apoptosis signaling pathway.
including NF-κB (Budd et al., 2006). It is well characterized that such translation inhibitors as cycloheximide diminish constitutive and NFκB-inducible c-FLIP expression and allow the activation of procaspase8 during death-receptor-mediated apoptosis (Kataoka, 2005). 3. TNF-α-converting enzyme (TACE) and ectodomain shedding TNF-α-converting enzyme (TACE), also referred to as a disintegrin and metalloproteinase 17, is a cell-surface metalloproteinase required
for the ectodomain shedding of many membrane-anchored proteins, such as cytokines (e.g., TNF-α) and receptors (e.g., TNF-R1 and TNF-R2) (Seals and Courtneidge, 2003). TACE plays a bifunctional role in the TNF-α signaling pathway in that the TACE-mediated ectodomain shedding generates soluble TNF-α as pro-inflammatory agonists and conversely downregulates cellsurface levels of TNF receptors, accompanied by the augmentation of soluble TNF receptors acting as anti-inflammatory antagonists (Scheller et al., 2011).
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TACE is ubiquitously expressed in various cell types and converted into its active form by the removal of its prodomain by furin proteinase in the Golgi compartment (Scheller et al., 2011). TACE activity is specifically regulated by an extracellular protein termed as the tissue inhibitor of metalloproteinase-3 (TIMP3). TIMP3 expression is upregulated by Jun proteins at the transcription level and controls the TACE-mediated TNF-α shedding during epidermal inflammation (Guinea-Viniegra et al., 2009). In response to various stimuli, extracellular signal-regulated kinase (ERK) and p38 MAP kinase phosphorylate the cytoplasmic domain of TACE at threonine 735 and thereby regulate the TACE-mediated ectodomain shedding (Díaz-Rodríguez et al., 2002; Liu et al., 2009; Soond et al., 2005; Xu and Derynck, 2010). In addition, the accessibility of the TACE catalytic site is regulated rapidly and reversibly by a mechanism that requires the transmembrane domain but not the cytoplasmic domain without depending on the prodomain removal (Le Gall et al., 2010). 4. Glutarimides and their biological properties Glutarimide antibiotics, such as cycloheximide, generally inhibit translation elongation by interfering with the translocation step. In a recently reported detailed mechanism, cycloheximide binds in the ribosomal E-site and stalls translocation by skewing the binding of deacylated tRNA to the E-site (Schneider-Poetsch et al., 2010b). As the most prominent translation inhibitor, cycloheximide has been widely used to sensitize many types of cells to the death-receptorinduced apoptosis (Kataoka, 2005). Cycloheximide is also known to cause rapid apoptosis in some cell types, including neutrophils, macrophages, and leukemia cell lines (Croons et al., 2007; Martin et al., 1990; Tang et al., 1999; Tsuchida et al., 1995). In human leukemia Jurkat cells, cycloheximide was shown to induce apoptosis via an FADD-dependent mechanism (Tang et al., 1999). In animal models, cycloheximide causes rapid induction of apoptosis in hepatocytes. This increases the mRNA levels of various genes for transcription factors as well as those related to apoptosis, ER stress, and inflammation (Ito et al., 2006). Acetoxycycloheximide, an acetoxyl analogue of cycloheximide, was found to induce apoptosis much more strongly than cycloheximide in Jurkat cells (Kadohara et al., 2005). In contrast to cycloheximide, acetoxycycloheximide dramatically induces the activation of ERK, c-Jun N-terminal kinase (JNK), and p38 MAP kinase (Kadohara et al., 2005). The JNK pathway plays an essential role in the regulation of apoptosis in response to various stresses and is required for the mitochondrial release of cytochrome c (Davis, 2000). JNK activation was found to mediate cytochrome c release during acetoxycycloheximideinduced apoptosis (Kadohara et al., 2005). As cycloheximide is known to induce MAP kinase activation at least to some extent (Croons et al., 2007; Iordanov et al., 1997; Kadohara et al., 2005; Sidhu and Omiecinski, 1998), it seems possible that MAP kinase signaling pathways are required for the cycloheximide-induced apoptosis. As the upstream transducers, double-stranded RNA-dependent protein kinase and hematopoietic cell kinase were identified to contribute to the activation of MAP kinase signaling pathways in response to trichothecene mycotoxins (e.g., deoxynivalenol) that interfere with the peptidyl transferase reaction (Pestka, 2010). Active caspase-8 cleaves the BH3-only protein Bid to generate its active form. Truncated Bid is translocated to mitochondria and initiates the mitochondrial release of cytochrome c into the cytosol, where cytochrome c, in turn, collaborates with adaptor protein Apaf-1 to activate initiator procaspase-9 (Danial and Korsmeyer, 2004). We recently found that Jurkat cells deficient in procaspase8 manifested inefficient mitochondrial release of pro-apoptotic proteins in response to acetoxycycloheximide; however, this was rescued by the reconstitution with catalytically inactive procaspase8 (Kadohara et al., 2009). These data supported the hypothesis that procaspase-8 mediates the mitochondrial release of pro-apoptotic
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proteins in a manner independent of its proteolytic activity during the acetoxycycloheximide-induced apoptosis. We also found that a portion of procaspase-8 was localized to mitochondria before and after exposure to acetoxycycloheximide (Kadohara et al., 2009). This is in agreement with the finding that cardiolipin anchors caspase8 at the contact sites between the inner and outer mitochondrial membranes (Gonzalvez et al., 2008). The molecular mechanism underlying the mediation of mitochondrial apoptosis signals during the acetoxycycloheximide-induced apoptosis by procaspase-8 remains to be clarified. Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface glycoprotein and its expression is drastically induced in an NF-κBdependent manner. In the course of screening for compounds that block the NF-κB signaling pathway, acetoxycycloheximide was initially identified to inhibit much more strongly ICAM-1 expression induced by TNF-α than that induced by IL-1 (Sugimoto et al., 2000). As the mechanism responsible for this selective inhibition, acetoxycycloheximide and, to a lesser extent, cycloheximide induced the ectodomain shedding of TNF-R1 by TACE via the activation of ERK and p38 MAP kinase, diminishing both apoptosis and NF-κB signaling pathways in response to TNF-α (Ogura et al., 2008a; Ogura et al., 2008b). Thus, translation inhibitors do not necessarily confer cell susceptibility to the TNF-α-induced apoptosis and in some cases, the combined treatment with TACE inhibitors or ERK and p38 MAP kinase inhibitors may be effective to promote the TNF-α-induced apoptosis. 5. Triene-ansamycins and their biological properties Ansamycins possess an aromatic moiety bridged by an aliphatic chain. They are classified into naphthalenoid ansamycins that generally inhibit RNA polymerase (e.g., rifamycin) and benzenoid ansamycins that exhibit more diverse functions (e.g., geldanamycin and herbimycin, which are Hsp90 inhibitors). The triene-ansamycin group of compounds belongs to benzenoid ansamycins and is characterized by the presence of a triene structure in the aliphatic chain. This group comprises various compounds, including mycotrienins (also termed as ansatrienins), trienomycins, and cytotrienins. The triene-ansamycin compounds were shown to exert various biological activities, such as antitumor activity, as well as the inhibition of phagocytosis, osteoclastic bone resorption, c-Src protein kinase, EGF receptor signaling, farnesyltransferase, NO production, and ERstress-induced X box-binding protein 1 (XBP1) activation (Feuerbach et al., 1995; Hara et al., 2000; Hosokawa et al., 1999; Kakeya et al., 1997; Kawamura et al., 2008; Kim et al., 2002; Magae et al., 1994; Sugita et al., 1982; Tashiro et al., 2007). Cytotrienin A has the common structural motifs of the trieneansamycin family plus an unusual aminocyclopropane carboxylic acid chain. Cytotrienin A was identified as an inducer of apoptosis in human leukemia HL-60 cells (Kakeya et al., 1997). Cytotrienin A induces the activation of protein kinases, including JNK, p38 MAP kinase, and p36 myelin basic protein, and the activation of these protein kinases is responsible for the induction of apoptosis (Kakeya et al., 1998; Watabe et al., 2000). Recently, cytotrienin A was shown to inhibit cellular protein synthesis (Lindqvist et al., 2010; Yamada et al., 2011a; Yamamoto et al., 2011). In translocation elongation, cytotrienin A interferes with the function of eukaryotic elongation factor 1A that delivers aminoacyl tRNA to the A-site of the ribosome (Lindqvist et al., 2010). Other triene-ansamycin family members, including mycotrienins, were found to inhibit cellular or cell-free protein synthesis (Yamada et al., 2011b; Yamamoto et al., 2011). These findings clearly indicate that the triene-ansamycin family is a novel class of translation inhibitors. XBP1 is a transcription factor that upregulates molecular chaperons to diminish the accumulation of unfolded proteins during ER stress. Inositol-requiring enzyme-1α is an endonuclease localized on the ER membrane and mediates the splicing of the precursor form
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of XBP1 mRNA to its active form. The translation inhibitor puromycin promotes premature peptide chain termination and releases incomplete nascent peptides from the ribosome (Yanagitani et al., 2011). Puromycin induces the accumulation of unfolded proteins, thereby promoting XBP1 mRNA splicing (Croons et al., 2008; Yamamoto et al., 2011). By contrast, cycloheximide does not induce the release of peptide chains from the ribosome and stabilizes polysomes (Schneider-Poetsch et al., 2010b). The triene-ansamycin compounds, including trierixin and quinotrierixin, were identified to inhibit ERstress-induced XBP1 activation (Kawamura et al., 2008; Tashiro et al., 2007). This is ascribed largely to the direct inhibition of translation in a manner similar to cycloheximide (Yamamoto et al., 2011). We have recently shown that mycotrienin II and cytotrienin A inhibit more strongly the cell-surface ICAM-1 expression induced by TNF-α than the expression induced by IL-1α (Yamada et al., 2011a; Yamada et al., 2011b). Acetoxycycloheximide and anisomycin, but neither puromycin nor emetine, inhibited the TNF-α-induced ICAM1 expression at lower concentrations than the IL-1-induced ICAM-1 expression (Yamada et al., 2011a). Cytotrienin A was found to induce the ectodomain shedding of TNF-R1 via the activation of ERK and p38 MAP kinase (Yamada et al., 2011a). This is in agreement with previous studies that cytotrienin A induces the activation of MAP kinase superfamily (Kakeya et al., 1998; Watabe et al., 2000), Thus, the triene-ansamycin family members are translation inhibitors that strongly induce ribotoxic stress response. 6. Conclusions and perspectives Translation inhibitors are highly useful bioprobes to analyze the contribution of translation to complex cellular responses and signaling pathways. Several types of translation inhibitors have been often used as strong inducers to trigger the activation of the MAP kinase superfamily. Recent studies by us and other groups have disclosed novel types of translation inhibitors that induce ribotoxic stress response, such as acetoxycycloheximide and the trieneansamycin family compounds. However, the detailed molecular mechanisms by which these translation inhibitors induce the activation of protein kinases and subsequently elicit various intracellular responses have been poorly characterized. The elucidation of those molecular mechanisms is expected to contribute to the discovery of unknown signaling pathways and cellular functions as well as the development of potential lead compounds for anti-cancer and antiinflammatory drugs. Acknowledgments This work was supported by a Grant-in-Aid for Scientific Research (KAKENHI) from Japan Society for the Promotion of Science (JSPS). References Bhoj, V.G., Chen, Z.J., 2009. Ubiquitylation in innate and adaptive immunity. Nature 458, 430–437. Budd, R.C., Yeh, W.C., Tschopp, J., 2006. cFLIP regulation of lymphocyte activation and development. Nat. Rev. Immunol. 6, 196–204. Croons, V., Martinet, W., Herman, A.G., Timmermans, J.P., De Meyer, G.R., 2007. Selective clearance of macrophages in atherosclerotic plaques by the protein synthesis inhibitor cycloheximide. J. Pharmacol. Exp. Ther. 320, 986–993. Croons, V., Martinet, W., Herman, A.G., De Meyer, G.R., 2008. Different effect of the protein synthesis inhibitors puromycin and cycloheximide on vascular smooth muscle cell viability. J. Pharmacol. Exp. Ther. 325, 824–832. Danial, N.N., Korsmeyer, S.J., 2004. Cell death: critical control points. Cell 116, 205–219. Davis, R.J., 2000. Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252. Díaz-Rodríguez, E., Montero, J.C., Esparís-Ogando, A., Yuste, L., Pandiella, A., 2002. Extracellular signal-regulated kinase phosphorylates tumor necrosis factor αconverting enzyme at threonine 735: a potential role in regulated shedding. Mol. Biol. Cell 13, 2031–2044. Feuerbach, D., Waelchli, R., Fehr, T., Feyen, J.H., 1995. Mycotrienins. A new class of potent inhibitors of osteoclastic bone resorption. J. Biol. Chem. 270, 25949–25955.
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Xu, P., Derynck, R., 2010. Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol. Cell 37, 551–566. Yamada, Y., Taketani, S., Osada, H., Kataoka, T., 2011a. Cytotrienin A, a translation inhibitor that induces ectodomain shedding of TNF receptor 1 via activation of ERK and p38 MAP kinase. Eur. J. Pharmacol. 667, 113–119. Yamada, Y., Tashiro, E., Taketani, S., Imoto, M., Kataoka, T., 2011b. Mycotrienin II, a translation inhibitor that prevents ICAM-1 expression induced by proinflammatory cytokines. J. Antibiot. 64, 361–366. Yamamoto, K., Tashiro, E., Imoto, M., 2011. Quinotrierixin inhibited ER stress-induced XBP1 mRNA splicing through inhibition of protein synthesis. Biosci. Biotechnol. Biochem. 75, 284–288. Yanagitani, K., Kimata, Y., Kadokura, H., Kohno, K., 2011. Translational pausing ensures membrane targeting and cytoplasmic splicing of XBP1u mRNA. Science 331, 586–589.