Commuting (to) suicide: An update on nucleocytoplasmic transport in

Patricia Grote, Karin Schaeuble, Elisa Ferrando-May"

Ulliversity of KOllstanz, Departmellt of Biology, Molecular Toxicology, P.O. Box X911, D 78457 KOllstall z, GermallY

Abstract

Commuting is the process of travelling between a place of residence and a place of work. In the context of biology, this expression evokes the continuous movement of macromolecules between different compartments of a eukaryotic cell. Transport in and out of the nucleus is a major example of intracellular commuting. This article discusses recent findings that substantiate the emerging link between nucleocytoplasmic transport and the signalling and execution of cell death.

KeYlVords: Caspase; ; DNA damage; Nuclear per~eability; Cellular stress; Ran; NFKB; GAPDH; PIDD; Virus

Interorganellar cross-talk has become a fundamental of the nuclear pore complex (NPC) I in dying cells, (2) issue in the field of cell death by apoptosis. Distinct cel­ mechanisms of nuclear uptake/release of individual apo­ lular organelles and compartments such as the mitochon­ ptosis mediators, and (3) stress-induced changes in global dria, the endoplasmic reticulum, the nucleus and the transport activity. The present mini review highlights plasma membrane can be the source of primary signals some recent results related to each of these three topics. that lead to cell killing [1,2]. Conversely, downstream For a more detailed introduction into the molecular effectors of cell death, primarily caspases, act at different biology of the NPC and the mechanisms of nuclear subcellular sites to accomplish the dismantling of cellular transport, several excellent review articles are available structures. This dual role as initiator and victim of death (e.g. [5 7]). signalling cascades is probably best exemplified by the , being on the one hand the origin of the cell's response to DNA damage, and on the other hand, Stress- and pathogen-induced NPC dysfunction a major substrate for the demolishing activity of the apoptotic execution machinery. Thus, the apparatus gov­ A recent comprehensive analysis of the fate of the NPC erning the movement of molecules across the nuclear in cell death by apoptosis [8] has confirmed and extended membrane has the potential to influence the cell death previous data on the caspase-mediated degradation of process on multiple levels. In fact, connections between nuclear pore [8 II]. According to these studies, nucleocytoplasmic transport and apoptosis have emerged both peripherally located nuclear pore proteins (Nups) as in the past and have been summarized in two recent arti­ well as two Nups within the NPC core are degraded, while cles [3,4]. In general, studies in the field have developed the overall structure of the pore remains intact. This is along three lines: (I) structural and functional alterations

I Abbreviations used: NPC, nuclear pore complex; PARP, poly (ADP) ribose polymerase; AIF, apoptosis inducing factor; GAPDH, glyceralde • Corresponding author. Fax: + 49 7531 884033. hyde 3 phosphate dehydrogenase; PIDD, p53 induced with a Email address:[email protected] (E. Ferrando May). death domain; NO, nitric oxide; CA V, chicken anaemia virus. 157

thought to cause the collapse of the permeability barrier as disruption of the PARP-l gene, confer neuroprotection and to inhibit active transport, but conclusive data on in cellular and animal models of ischemia and stroke the functional consequences of caspase-mediated NPC [27,28]. Two papers have now pinpointed the molecular cleavage are still lacking. Other studies have proposed that mechanism of PAR-mediated cytotoxicity: the PAR poly­ NPC permeability may be altered in cells committed to die mer itself acts as a death signal causing neuronal demise in the absence of any apparent disruption of nuclear pore · when its concentration is increased either by transfection proteins [1 2,13] suggesting the existence of other mecha­ or by downregulating the expression of PARG, the glyco­ nisms of NPC dysfunction. hydrolase responsible for PAR catabolism [29]. A key Examples for such alternative, caspase-independent mediator of PAR-induced cell death is Apoptosis-Inducing pathways for breaking the nucleocytoplasmic barrier come Factor (AI F), a mitochondrial flavoprotein which was pre­ from virus-infected cells. The poliovirus 2A protease, for viously shown to move to the nucleus during apoptosis and example, mediates, directly or indirectly, the cleavage of trigger chromatin condensation as well as high-molecular the nucleoporins Nupl53 and p62. Most remarkably and weight DNA fragmentation [30]. In the absence of in contrast to what has been reported for apoptotic cells, PARP-l, the mitochondrial release of AIF is abrogated virus infection is accompanied by structural disruption of and cells are protected from death triggered by DNA dam­ the NPC as shown by electron microscopy [14 16]. In age, oxidative stress and excitotoxic insults [31]. Dawson yeast, degradation of nucleoporins as a consequence of oxi­ and co-workers have now demonstrated that the PAR dative insult was shown to be mediated by Pep4p, a cathep­ polymer acts as an AIF releasing factor [32]. In agreement sin 0 homolog [17]. Here again, nuclear envelope with its role as nuclear-mitochondrial messenger, PAR permeability increased prior to the degradat'ion of nucleo­ appears in the cytosol and at the mitochondria of cortical porins, supporting the notion that NPC function may be neurons after NMDA receptor stimulation. An open and altered without damage to its components. In fact, these very relevant question arising in this context concerns the observations are consistent with the notion of the NPC mechanism of PAR's nuclear extrusion. Only PAR poly­ as a dynamic, adaptive channel, whose conformation and mers of at least 60 ADP-ribose units, corresponding to a functional properties are highly sensitive to changes in cel­ minimum molecular weight of 33.6 kDa, display significant lular activity [5]. Considering the diversity of pathways toxicity. Larger polymers can arise in vivo as a consequence engaged by pathogens, by environmental noxa and by of PARP-l activation [33,34]. In addition, it is not yet clear developmental cues, all potentially culminating in cell whether the deadly polymers exit the nucleus as free mole­ death, it is not surprising to observe variations in the mode cules or associated with a (protein) carrier. In any case, of NE permeabilization depending on the death model sys­ propagation of this signal is likely to be restricted by the tem. Beside proteases, alterations of NPC structure and size exclusion limit of the NPC which under normal condi­ function during apoptosis could arise e.g. via calcium tions is in the range of about 40 kDa. Therefore, small vari­ [18], or hydrophobic compounds such as proapoptotic lipid ations in NPC structure could have a huge impact on the mediators [19,20] or the cytoskeleton [21,22]. The fact efficiency of PAR signalling to the mitochondria. It is inter­ that multiple and possibly overlapping pathways may lead esting in this respect that an increase in NPC permeability to the breakdown of the nucleocytoplasmic barrier in has been recently observed in cerebellar granule neurons apoptosis marks a distinction between this process and undergoing cell death by excitotoxicity (Bano, D., and . mitotic nuclear envelope disassembly, the latter ensuing Nicotera P., pers. communication) . from a specifically triggered, precisely orchestrated, and unique sequence of signalling events [23]. p53-induced protein with a death domain (PIDD)

Apoptotic players moving in and out of the nucleus PlOD is a p53-inducible gene encoding a novel death domain-containing protein [35,36]. Initially characterized Poly-( ADP)-ribose (PAR) as a proapoptotic factor involved in the activation of cas­ pase-2 after genotoxic damage [37,38], PlOD was subse­ PAR is one of the most interesting newcomers to the quently determined to participate in cell survival via the growing family of molecules that commute from and to NFK-B pathway [39]. The molecular basis for these oppos­ the nucleus in cell death. Protein modification by poly­ ing roles of PlOD lies in the interaction with different (ADP)-ribose results from the activity of the poly-(ADP)­ adaptors resulting in the formation of two distinct macro­ ribose polymerase (PARP) family of enzymes. It has been molecular complexes, also termed PIDDosomes: RAIDD initially described as an immediate response to DNA dam­ is essential for building the platform for activation of cas­ age involved in the activation of several DNA repair path­ pase-2, while RIPI bridges the interaction of PlOD with ways. Additionally, and in particular in the nervous NEMO, a regulatory subunit of the IkB kinase complex. system, poly-(ADP)-ribosylation has been shown to medi­ The latter results in augmented SUMO-modification of ate cell injury in response to ischemia and oxidative stress NEMO and subsequent activation of NFK-B which then (for reviews see [24 26]) . Pharmacological inhibitors of triggers the expression of antiapoptotic genes (for review PARP-l, the founding member of the PARP family, as well see also [40]). The activity of PlOD as a molecular switch 158

between life and death is controlled by autoproteolysis and primarily in the nucleus [46]. As demonstrated by recently by the nucleocytoplasmic distribution of PIDD fragments, published heterokaryon experiments [47], Apoptin is a bona as described by a recent paper from J. Tschopp's group fide nucleocytoplasmic shuttling protein possessing signals [41]. According to this model, PIDD is cleaved by autopro­ for nuclear import (NLS) and export (NES). Transformed teolysis in two fragments with distinct functions: PIDD-C, cells display a cellular activity which negatively regulates which is generated by an initial autoproteolytic step and the NES and favours the NLS, resulting in nuclear accumu­ PIDD-CC a shorter fragment, whose formation requires lation. of a threonine residue adjacent to a second, delayed cleavage event. The kinetics of PIDD the N ES has been proposed as a candidate mechanism, since autoprocessing appear to depend strongly on the dose of this is observed only in tumour ce lls and has been shown to the genotoxic insult: at high level of damage, the time delay inhibit nuclear export [46,48]. Intriguingly, the nuclear local­ between PIDD-C and PIDD-CC formation disappears and ization of Apoptin seems absolutely dependent on the spe­ both fragments are induced simultaneously. Crucially, the cific sequence of the Apoptin NES, which also harbours a only species showing interaction with RIP I, thus bearing multimerization domain: Apoptin mutants in which this the potential to initiate the modifications of NEMO that sequence has been substituted for the NES of the HIV-Rev are required for NFK-B activation, is PIDD-C. In accor­ protein show the identical diffuse localization in both tumour dance with this, only PIDD-C is able to undergo nuclear and primary cells. On the other hand, several studies have translocation which is necessary for NEMO modification, demonstrated that nuclear localization per se is not sufficient following DNA damage. Only the shorter PIDD-CC frag­ for Apoptin-mediated cell death. A recent elegant study [47] ment, on the other hand was found associated with has put forward a model to reconcile, at least in part, some of RAIDD and was required for the activation of caspase-2. the controversial observations concerning Apoptin's func­ An interesting open question in this context concerns the tion: according to this model, the critical factor in cell killing trigger for the nuclear uptake of PIDD-C, since this frag­ by Apoptin is not the steady state localization but rather its ment is formed almost immediately after synthesis of the ability to shuttle between the nucleus and the cytoplasm. full-length protein but remains restricted to the cytoplasm Only Apoptin with functional transport signals (NES and unless the cells suffer DNA damage. The proposed NLS) is able to bind APCI , a mitotic regulator, and recruit unmasking of a nuclear localization site may thus require it to PML bodies. In this way, Apoptin could mediate inhibi­ not only autoproteolysis but also a second damage-specific tion of APCI resulting in G2/M arrest and subsequent event. Altogether, the PIDD story provides a compelling apoptosis. example for the selective induction of signalling pathways by regulated subcellular localization. Inhibitors of apoptosis

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) Also, the activity of negative regulators of apoptosis is controlled by their nucleocytoplasmic localization. This GAPDH is a well-known glycolytic enzyme which was has been investigated in detail in the case of XIAP and shown to translocate to the nucleus in a number of model sys­ the clAPs (for a review, see [4]). In general, nuclear locali­ tems of apoptosis [42]. Nuclear accumulation of GAPDH zation of these inhibitors is regarded as a way to seclude has been linked to cytotoxicity [43], but the molecular events them from their targets, active caspases present in the cyto­ underlying GAPDH-mediated cell death have been elusive. plasm. While this may bear significance forXIAP, the only Recently, S-nitrosylation of GAPDH by nitric oxide (NO) member of the family being a bona fide caspase inhibitor was reported to elicit a signalling pathway culminating in cell [49], it is less likely to playa significant role in the antiap­ death [44]. Modification abolishes the catalytic activity and optotic action of the clAPs, whose mechanism of action is confers GAPDH with the ability to bind Siah, an E3 ubiqui­ less clear but may involve the ubiquitination and proteaso­ tin ligase. By virtue of Siah's nuclear localization signal, the mal degradation of caspases and other targets. In fact, complex translocates to the nucleus. Here, Siah is protected enforced nuclear location of clAP I does not interfere with from its otherwise very rapid turnover through the interac­ its ability to prevent apoptosis [50]. tion with GAPDH. Stabilized Siah induces the degradation Recently, a nuclear export signal has been identified in of diverse target proteins and ultimately cell death. one member of the BcI-2 family of apoptosis inhibitors, Bok [51]. Mutation of this NES results in nuclear accumu­ Apoptin lation and increases Bok's proapoptotic function. This is the first example of regulated nucleocytoplasmic shuttling Apoptin is a small protein from the chicken anaemia virus of a bcl-2 family member. (CA V), which has attracted attention because it selectively induces apoptosis in tumor cells while leaving normal cells Stress-induced alterations of nucleocytoplasmic transport: intact [45]. This tumor-specific killing activity has been cause or consequence of cell death? related to cell-type dependent differences in its nucleocyto­ plasmic distribution. In primary cells, Apoptin is localized Among the first alterations of the nucleocytoplasmic to the cytoplasm, while in transformed cells it is found transport machinery observed under conditions of cellular 159

Table I Nucleocytoplasmic transport of apoptosis related factors Factor Translocation direction in Signals for active transport, regulation mechanisms Involvement of References apoptosis caspases AIF mito ---) nuc NLS, cytoplasmic retention (hsp70) Casp. indep. [30,60] WOX I mito ---) nuc NLS n.d. [61] Endo G mito ---) nuc No obvious transport signals n.d. [62] ARTS mito ---) nuc n.d. Casp. dep. [63,64] PAK5 mito ---) nllc NLS, NES n.d. [65] DEDD cyto ---) nliC NLS, NES, lIbiqllitination cytoplasmic retention Casp. dep. [55 ,66] (cytokeratins) TRADD cyto ---) nuc NLS, NES cytoplasmic retention (cytokeratins) n.d. [67,68] Apaf I cyto ---) nuc Mediated by nucling n.d. [69] 010 I cyto ---) nliC NLS, phosphorylation n.d. [70] GAPDH cyto ---) nllc Mediated by siah I n.d. [44] MSTI cyto ---) nllc NLS, NES, phosphorylation Casp. dep. [7 1,72] PAK2 cyto ---) nuc NLS, NES Casp. dep. [73] Helicard cyto ---) nuc n.d. Casp. dep. [74] CAD/DFF40 cyto ---) nuc NLS Casp. dep. [75.76] HDAC4 cyto ---) nuc NLS, NES Casp. dep. [77,78] Apoptin cyto ---) nliC NES, NLS n.d. [46 48] PTEN cyto ---) nllc NLS n.d. [58,79] Caspase 3 cyto ---) nliC Mediated by AKAP95 n.d. [80] DAXX nuc ---) cyto NLS, NES, phosphorylation n.d. [81,82] Nur77/TR3 nuc ---) mito NLS, NES, phosphorylation n.d. [83 85] p53 nllc---) mito NLS, NES, lIbiqllitination n.d. [86] Histone H 1.2 nllc---) mito Active import by importin p/importin 7 Casp. indep. [87] Caspase 2 nllc---) mito NLS Casp. dep. [88,89] PAR nuc ---) mito n.d. Casp. indep. [29,32] FADD cyto +-> nllc NLS, NES (exportin 5) , phosphorylation n.d. [90,91] PEA 15 cyto +-> nllc NES n.d. [92,93]

stress is an increase of the cytoplasmic concentration of respect, extrusion of Ran out of the nucleus may be Ran, a small GTPase controlling the direction of nuclear regarded as a strategy to promote survival by counteract­ transport. In unperturbed cells, Ran localizes predomi­ ing the relay of death signals to the nucleus. There is no evi­ nantly to the nucleus as Ran-GTP, whereas it is found in dence yet to support this mechanism. Nevertheless, one can the cytoplasm after treatment with different apoptosis­ predict that it will most likely play a role in cells which inducing agents (for a summary see [3]). Ran exiting the loose the ability to produce sufficient ATP at an early stage nucleus is converted to the GDP-bound form by its after injury and will thus not die by typical apoptosis. In GTPase activating protein, RanGAP, located at the cyto­ fact, preservation of ATP levels is a distinguishing feature plasmic side of the NPC. Thus, leakage of Ran out of the of apoptotic cell death [57), and nuclear import was shown nucleus is expected to deplete the cellular pool of Ran­ to be functional in different model systems of apoptosis [58, GTP. Reduced levels of Ran-GTP, in turn, are responsible and own unpublished observations). for the inhibition of nuclear import that is observed in A TP On the other hand, a protracted and substantial inhibi­ depleted cells [52]. In line with these results, Yasuda et ai., tion of can per se trigger cell death, as have reported that the appearance of cytoplasmic Ran fol­ shown for CC3, a proapoptotic protein capable of forming lowing oxidative stress, heat shock and UV irradiation is stable complexes with import receptors and blocking multi­ the consequence of a decreased intracellular ATP pool ple nuclear import pathways. Whether alterations of the [53). Import inhibition in cells with low Ran-GTP corre­ nuclear transport system may be cause or consequence, lates with nuclear accumulation of the classical import fac­ antagonize or exacerbate cell death, is thus an intricate tor importin-ex [13,52,53). The physiological outcome of question. While we are appreciating that nuclear transport importin-ex nuclear sequestration may vary depending on is an integral part of death signalling, it also becomes clear which of the six known isoforms of this protein is affected that death pathways may be regplated by nuclear transport [54) and which substrates thus fail to be transported. For at different levels and with different outcomes depending on example, reduced nuclear uptake of proapoptotic factors the cellular context and the type of insult. with a classical NLS, such as AIF [30) or DEDD [55) should have a protective effect. Consistent with this Conclusion assumption is the observation that partial inhibition of nuclear import by WGA, GTP-yS or excess amounts of There is plenty of evidence in the literature that both the NTF2 or importin-ex may delay cell demise [56). In this nuclear uptake and release of apoptotic factors play 160

important roles in the initiation and execution of the apop­ [24] A. Burkle, Bioessays 23 (2001) 795 806. totic program. The interest in elucidating the mechanisms [25] V. Schreiber, F. Dantzer, J.e. Arne, G. de Murcia, Nat. Rev. Mol. Cell BioI. 7 (2006) 517 528. involved in regulating the subcellular localization of such [26] D.W. Koh, T.M. Dawson, V.L. Dawson, Pharmacol. Res. 52 (2005) factors is thus steadily increasing. During the past year, 5 14. several newcomers have joined the list of apoptotic players [27] J. Zhang, V.L. Dawson, T.M. Dawson, S.H. Snyder, Science 263 whose function is controlled by nucleocytoplasmic trans­ (1994) 687 689. port (see Table I). More remarkably, novel mechanisms [28] M.J. Eliasson, K. Sampei, A.S. Mandir, P.D. Hum, R.J. Traystman, J. Bao, A. Pieper, Z.Q. Wang, T.M. Dawson, S.H . Snyder, V.L. for the relay of apoptotic signals from and to the nucleus Dawson, Nat. Med . 3 (1997) 1089 1095. have emerged. This is the case for PAR, which represents [29] SA Andrabi, N.S. Kim , S.W. Yu, H. Wang, D.W. Koh, M. Sasaki, a novel type of nucleo-mitochondrial messenger molecule, J.A. Klaus, T. Otsuka, Z. Zhang, R. e. Koehler, P.O. Hum, G.G . and for GAPDH, the erstwhile enigmatic promoter of ce ll Poirier, V.L. Dawso n, T.M. Dawson, Proc. Natl. Acad. Sci. USA 103 death in the nucleus, now identified as an interactor of the (2006) 18308 18313. [30] S.A. Susin, H.K. Lorenzo, N. Zamza mi, I. Marzo, B.E. Snow, G.M. E3 ubiquitin ligase Siah l. On the other hand, as the bio­ Brothers, 1. Mangion, E. lacotot, P. Costantini, M. Loeffler, N. physical principles that govern the passage through the Larochette, D.R. Goodlett, R. Aebersold , D.P. Siderovski, J.M. nuclear pore become accessible [59] significant progress is Penninger, G. Kroemer, Nature 397 (1999) 44 1 446. to be expected in our understanding of how changes in cel­ [31] S.W. Yu, H. Wang, M.F. Poitras, C. Coombs, W.J. Bowers, H.J. lular activity may translate into alterations of nuclear Federoff, G.G. Poirier, T.M. Dawson, V.L. Dawson, Science 297 (2002) 259 263. transport. [32] S.W. Yu, SA Andrabi, H. Wang, N.S. Kim, G .G . Poirier, T.M. Dawson, V.L. Dawson, Proc. Natl. Acad. Sci. USA 103 (2006) Acknowledgments 183 14 18319. [33] R. Alvarez Gonzalez, J. Moss, C. Niedergang, F.R. Althaus, We wish to thank Evelyn O'Brien for critical reading of Biochemistry 27 (1988) 5378 5383. the manuscript and J6rg Fahrer for helpful informations [34] R. Meyer, in: Burkle, A., (Ed.), Poly(ADP ribosyl)ation, Landes Bioscience, Georgetown, TX, USA 2005. on PAR metabolism. [35] Y. Lin, W. Ma, S. Benchimol, Nat. Genet 26 (2000) 122 127. [36] J.B. Telliez, K.M. Bean, L.L. Lin, Biochim. Biophys. Acta 1478 References (2000) 280 288. [3 7] A. Tinel, J. Tschopp, Science 304 (2004) 843 846. [I] K.F. Ferri, G. Kroemer, Nat. Cell BioI. 3 (2001) E255 E263. [38] e. Berube, L.M. Boucher, W. Ma, A. Wakeham, L. Salmena, R. [2] J.J. Lemasters, Gastroenterology 129 (2005) 35 1 360. Hakem, W.e. Yeh, T.W. Mak, S. Benchimol, Proc. Natl. Acad. Sci. [3] E. Ferrando May, Cell Death Differ. 12 (2005) 1263 1276. USA 102 (2005) 14314 14320. [4] B. Fahrenkrog, Can. J. Physiol. Pharmacol. 84 (2006) 279 286. [39] S. Janssens, A. Tinel, S. Lippens, J. Tschopp, Cell 123 (2005) [5] E. J. Tran, S.R. Wente, Cell 125 (2006) 1041 1053. 1079 1092. [6] R. Peters, Methods Mol. BioI. 322 (2006) 235 258. [40] H. Sebban, S. Yamaoka, G. Courtois, Trends Cell BioI. 16 (2006) [7] L.F. Pemberton, B.M. Paschal, Traffic 6 (2005) 187 198. 569 577. [8] M. Patre, A. Tabbert, D. Hermann, H. Walczak, H.R. Rackwitz, [41] A. Tinel, S. Janssens, S. Lippens, S. Cuen in , E. Logette, B. Jaccard, V.e. Cordes, E. Ferrando May, J. BioI. Chern. 28 1 (2006) 1296 1304. M. Quadroni, J. Tschopp, EMBO J. (2006). [9] B. Buendia, A. Santa Maria, J.C. Courvalin , J. Cell Sci. 112 (1999) [42] M.A. Sirover, Biochim. Biophys. Acta 1432 (1999) 159 184. 1743 1753. [43] A. Sawa, A.A. Khan, L.D. Hester, S.H. Snyder, Proc. Natl. Acad. [10] M. Kihlmark, G. Imreh, E. Hallberg, J. Cell Sci. 114 (200 1) Sci. USA 94 (1997) 11669 11674. 3643 3653. [44] M.R. Hara, N. Agrawal, S.F. Kim, M.B. Cascio, M. Fujimuro, Y. [II] M. Kihlm ark, e. Rustum, e. Eriksson, M. Beckman, K. Iverfeldt, E. Ozeki, M. Takahashi, J.H. Cheah, S.K. Tankou, L.D. Hester, C.D. Hallberg, Exp. Cell Res. 293 (2004) 346 356. Ferris, S.D. Hayward, S.H. Snyder, A. Sawa, Nat. Cell BioI. 7 (2005) [12] L. Faleiro, Y. Lazebnik, J. Cell BioI. 151 (2000) 95 1 959. 665 674. [13] E. Ferrando May, V. Cordes, I. Biller, D. Gorlich, J. Mirkovic, P. [45] A.A. Danen Van Oorschot, D.F. Fischer, J.M. Grimbergen, B. Nicotera, Cell Death Differ. 8 (200 1) 495 505. Klein, S. Zhuang, J.H. Falkenburg, e. Backendorf, P.H. Quax, [14] K.E. Gustin, P. Sarnow, J. Virol. 76 (2002) 8787 8796. A.J. Van der Eb, M.H. Noteborn, Proc. Natl. Acad. Sci USA 94 [15] G.A. Belov, P.V. Lidsky, O.V . Mikitas, D. Egger, K.A. Lukyanov, K. (1997) 5843 5847. Bienz, V.I. Agol, J. Virol. 78 (2004) 10166 10177. [46] A.A. Danen Van Oorschot, Y.H. Zhang, S.R. Leliveld, J.L. Rohn, [16] P.V . Lidsky, S. Hato, M.V. Bardina, A.G. Aminev, A.e. Palmenberg, M.e. Seelen, M.W. Bolk, A. Van Zon, S.J. Erkeland, J.P. Abrahams, E.V. Sheval, V.Y. Polyakov, F.J. van Kuppeveld, V.1. Agol, J. Virol. D. Mumberg, M.H. Notebom, J. BioI. Chern. 278 (2003) 80 (2006) 2705 27 17. 27729 27736. [17] D.A. Mason, N. Shulga, S. Undavai, E. Ferrando May, M.F. [47] D.W. Heilman, J.G. Teodoro, M.R. Green, J. Virol. 80 (2006) Rexach, D.S. Goldfarb, FEMS Yeast Res. 5 (2005) 1237 1251. 7535 7545. [18] E.S. Erickson, O.L. MOOl'en, D. Moore, J.R. Krogmeier, R.e. Dunn, [48]I.K. Poon, e. Oro, M.M. Dias, J. Zhang, D.A. Jans, Cancer Res. 65 Can. J. Physiol. Pharmacol. 84 (2006) 309 318. (2005) 7059 7064. [19] V. Shahin, Bioessays 28 (2006) 935 942. [49] B.P. Eckelman, G.S. Sa lvesen, F.L. Scott, EMBO Rep. 7 (2006) [20] K. Ribbeck, D. Gorlich, EMBO J. 21 (2002) 2664 267 1. 988 994. [21] E. Kiseleva, S.P. Drummond, M.W. Goldberg, S.A. Rutherford, T.D. [50] B. Vischi oni, G. Giaccone, S.W. Span, F.A. Kruyt, J.A. Rodriguez, Allen, K.L. Wilson, J. Cell Sci. (2004). Exp. Cell Res. 298 (2004) 535 548. [22] D.R. Croft, M.L. Coleman, S. Li, D. Robertson, T. Sullivan, e.L. [51] G. Bartholomeusz, Y. Wu , M. Ali Seyed, W. Xia, K.Y. Kwong, G. Stewart, M.F. Olson, J. Cell BioI. 168 (2005) 245 255. Hortobagyi, M.e. Hung, Mol. Carcinog. 45 (2006) 73 83. [23] A. Margalit, S. Vlcek, Y. Gruenbaum, R. Foisner, J. Cell Biochem. 95 [52] E.D. Schwoebel, T.H. Ho, M.S. Moore, J. Cell BioI. 157 (2002) (2005) 454 465. 963 974. 161

[53) Y. Yasuda, Y. Miyamoto, T. Saiwaki, Y. Yoneda, Exp. Cell Res. 312 [73] R. Jakobi, e.e. McCarthy, M.A. Koeppel, D.K . Stringer, J Bioi (2006) 512 520. Chem 278 (2003) 38675 38685. [54) e. Quensel, B. Friedrich, T. Sommer, E. Hartmann, M. Kohler, Mol. [74] M. Kovacsovics, F. Martinon, O. Micheau , J.L. Bodmer, Cell BioI. 24 (2004) 10246 10255. K. Hofmann, J. Tschopp, Curr Bioi 12 (2002) 838 843. [55) A.H. Stegh, O. Schickling, A. Ehret, e. Scaffidi, e. Peterhansel , T.G. [75] M. Enari, H. Sakahi ra, H. Yokoyama, K. Okawa, A. Iwamatsu, Hofmann, I. Grummt, P.H. Krammer, M.E. Peter, EMBO J. 17 S. Nagata, Nature 391 (1998) 43 50. (1998) 5974 5986. [76] S. Nagata, H. Nagase, K. Kawane, N. Mukae, H. Fukuyama, Cell [56) N. Yasuhara, Y. Eguchi, T. Tachibana, N. imamoto, Y. Yoneda, Y. Death Differ 10 (2003) 108 116. Tsujimoto, Genes Cells 2 (1997) 55 64 . [77] G. Paroni, M. Mizzau, e. Henderson, G. Del Sal, e. Schneider, [57) P. Nicotera, M. Leist, E. Ferrando May, Biochem. Soc. Symp. 66 e. Brancolini, Mol Bioi Cell 15 (2004) 2804 28 18. (1999) 69 73. [78] A.H. Wang, X.J. Yang, Mol Cell Bioi 21 (2001) 5992 6005. [58) A. Gil, A. Andres Pons, E. Fernandez, M. Valiente, J. Torres, J. [79] J.H. Chung, M. E. Ginn Pease, e. Eng, Cancer Res 65 (2005) Cervera, R. Pulido, Mol. BioI. Cell 17 (2006) 4002 4013. 4108 4 11 6. [59) S. Frey, R.P. Richter, D. Gorlich, Science 314 (200g) 815 817. [80] S. Kamada, U. Kikkawa, Y. Tsujimoto, T. Hunter, Mol Cell Bioi 25 [60) S. Gurbuxani, E. Schmitt, C. Cande, A. Parcellier, A. Hammann, (2005) 9469 9477. E. Daugas, I. Kouranti, C. Spahr, A. Pance, G. Kroemer, C. Garrido, [81] J.1 . Song, Y.1. Lee, J Bioi Chem 279 (2004) 30573 30578. Oncogene 22 (2003) 6669 6678. [82] J.1 . Song, Y.1. Lee, J Bioi Chem 278 (2003) 47245 47252. [61) N.S. Chang, J. Doherty, A. Ensign, J Bioi Chem 278 (2003) [83] H. Li, S.K. Kolluri, J. Gu, M.1. Dawson, X. Cao, P.O. Hobbs, B. Lin, 9195 9202. G. Chen, J. Lu, F. Lin , Z. Xie, J.A. Fontana, J.e. Reed, X. Zhang, [62) L.Y . Li, X. Luo, X. Wang, Nature 41 2 (200 1) 95 99. Science 289 (2000) 11 59 11 64. [63) S. Larisch, Y. Vi , R. Lotan, H. Kerner, S. Eimerl, W. Tony Parks, [84] A.1 . Wilson, D. Arango, J.M. Mariadason, B.G. Heerdt, Y. Gottfried, S. Birkey Reffey, M.P. de Caestecker, D. Danielpour, L.H. Augenlicht, Cancer Res 63 (2003) 540 1 5407. N. Book Melamed, R. Timberg, e.S. Duckett, R.1. Lechleider, [85] Y.H. Han, X. Cao, B. Lin, F. Lin, S.K. Kolluri, J. Stebbins, J.e. Reed, H. Steller, J. Orty, S.1 . Kim, A.B. Roberts, Nat Cell Bioi 2 (2000) M.I. Dawson, X.K. Zhang, Oncogene 25 (2006) 2974 2986. 915 92 1. [86] N.D. Marchenko, A. Zaika, U.M. Moll, J Bioi Chem 275 (2000) [64) Y. Gottfried, A. Rotem, R. Lotan, H. Steller, S. Larisch, EMBO J. 23 16202 162 12. (2004) 1627 1635. [87] A. Konishi, S. Shimizu , J. Hirota, T. Takao, Y. Fan, Y. Matsuoka, [65) S. Cotteret, J. Chern off, Mol Cell Bioi 26 (2006) 3215 3230. L. Zhang, Y. Yoneda, Y. Fujii , A.1. Skoultchi , Y. Ts ujimoto, Cell 114 [66) J.e. Lee, O. Schick ling, A.H. Stegh, R.G. Oshima, D. Dinsdale, (2003) 673 688 . G.M. Cohen, M.E. Peter, J Cell Bioi 158 (2002) 1051 1066. [88] G . Paroni, e. Henderson, e. Schneider, C. Brancolini, J Bioi Chem [67) M. Morgan, J. Thorburn, P.P. Pandolfi, A. Thorburn, J Cell Bioi 157 277 (2002) 15147 15161 . (2002) 975 984. [89] J.D. Robertson, V. Gogvadze, A. Kropotov, H. Vakifahmetoglu, [68] H. inada, I. izawa, M. Nishizawa, E. Fujita, T. Kiyono, B. Zhivotovsky, S. Orrenius, EMBO Rep 5 (2004) 643 648. T. Takahashi, T. Momoi, M. Inagaki, J Cell Bioi 155 (2001) [90] M. Gomez Angelats, J.A. Cidlowski, Cell Death Differ 10 (2003) 415 426. 79 1 797. [69] T. Sakai, L. Liu, X. Teng, R. Mukai Sakai, H. Shimada, R. Kaji, [91] R.A. Screaton, S. Kiessling, 0.1. Sansom, e.B. Millar, K. Maddison, T. Mitani, M. Matsumoto, K. Toida, K. ishimura, Y. Shishido, A. Bird, A.R. Clarke, S.M. Frisch, Proc Natl Acad Sci USA 100 T.W. Mak, K. Fukui, J Bioi Chem 279 (2004) 4 11 31 4 1140. (2003) 52 11 5216. [70) D. Garcia Domingo, D. Ramirez, G. Gonzalez de Buitrago, [92] H. Renganathan, H. Vaidyanathan, A. Knapinska, J.W. Ramos, A.e. Martinez, Mol Cell Bioi 23 (2003) 32 16 3225. Biochem J. 390 (2005) 729 735. [71) S. Ura, N. Masuyama, J.D. Graves, Y. Gotoh, Proc Natl Acad Sci [93] E. Formstecher, J.W. Ramos, M. Fauquet, D.A. Calderwood, USA 98 (2001) 10148 10153. J. C. Hsieh, B. Canton, X.T. Nguyen, J.Y. Bamier, J. Camonis, [72] K.K. Lee, S. Yonehara, J Bioi Chem 277 (2002) 1235 1 12358. M.H. Ginsberg, H. Chneiweiss, Dev Cell I (2001) 239 250.