Mutagenesis Advance Access published online on October 1, 2008
Mutagenesis, doi:10.1093/mutage/gen056
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Signalling loops and linear pathways: NF-
B activation in response to genotoxic stress
Department of Radiobiology and Health Protection, Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland
The signalling loop concept was introduced in 1991 to explain activation of membrane and cytoplasmic kinases in response to DNA damage inflicted by ionizing radiation. Damage to the chromosomal DNA was thought to provide a primary signal and a secondary signal from a nucleus to cytoplasm was assumed. This scenario was confirmed although not as originally proposed. A complex of nuclear factor-
B (NF-B) essential modulator and ataxia telangiectasia-mutated kinase activated by genotoxic agents is sent to cytoplasm, prompting nuclear translocation of the active transcription factor NF-B. In parallel, linear signalling pathways are initiated in the cytoplasm, mostly by reactive oxygen species, resulting in NF-B activation and nuclear translocation. The choice of NF-B activation pathway and the extent of activation of various pathways may be influenced by the relative degree of damage inflicted by genotoxic agents in the nuclear and cytoplasmic compartments. The ultimate pattern of cellular response is determined by availability, abundance and localization of the proteins participating in the signal transduction.
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Introduction |
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 Top Introduction The DNA DSB activated...The two-faced PIDDROS-induced NF-{kappa}B...Concluding remarksFundingReferences |
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A concept of signalling loop was introduced by Weichselbaum et al. (1
) in 1991 to explain activation of membrane and cytoplasmic kinases in response to DNA damage inflicted by ionizing radiation. As the damage (alarm) signal was thought to originate in the chromatin containing the damaged DNA, it was assumed that a secondary signal was sent from the nucleus to the cytoplasm to activate a kinase cascade to return the signal to the nucleus and turn on transcription of specific genes to repair a particular type of damage. The hypothesis predicted involvement of the signalling pathways used in cellular response to stress or mitogenic stimuli, in returning of the signal to the nucleus.
The signalling loop concept (presented in Figure 1) also served as a working hypothesis in studies on the mechanism of radio adaptation (2–4). The adaptive response of human lymphocytes to DNA damage (5) could be prevented by treatment with protein kinase C (PKC) inhibitor, calcium antagonists or anti-CD38 antibody. Since PKC usually resides in cytosol or plasma membrane (6) and CD38 is a plasma membrane-located cyclic adenosine diphosphoribose cyclase, a calcium-releasing agent, the hypothesis offered a satisfactory explanation of the experimental results. However, with the advances in cellular biology, it became clear that signalling cascades can be activated directly by reactive oxygen species (ROS) produced by ionizing as well as ultraviolet (UV) radiation, hydrogen peroxide (7) and pro-oxidant chemical agents, e.g. quinones (8). Part of the mechanism is inactivation of cytoplasmic protein phosphatases (9). The active (catalytic) sites of these enzymes contain nucleophilic cysteine residues, highly susceptible to oxidation [reviewed in (10,11)]. Inactivation of phosphatases shifts the equilibrium point between phosphorylated and dephosphorylated forms of receptors or cytosolic kinase molecules that initiate linear signalling pathways aimed at the nucleus.
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Thus, cytoplasm-to-nucleus signals responding to ionizing radiation or other ROS-generating agents do not require special messengers. Nevertheless, some DNA-damaging agents initiate cytoplasmic responses although their activity is strictly limited to the nucleus. For example, a genotoxic agent camptothecin (CPT) inactivates topoisomerase I with no involvement of ROS and produces DNA double strand breaks (DSB) during DNA replication with activation of nuclear factor-
B (NF-B) (12,13). Investigation of the cellular response to CPT and other DSB-generating agents led to a discovery of a signalling loop involving ataxia telangiectasia-mutated (ATM) kinase as a factor responding to DNA damage and NF-B as the cytoplasmic messenger that activates transcription within the nuclear genome.
NF-B is a family of inducible transcription factors that activate a large number of genes and may even turn on the entire gene expression programmes. The NF-B-related signalling is activated in such diverse cellular events as stress response, proliferation, inflammation, embryonic development and apoptosis. The signalling is response specific and involves various homo- or heterodimer combinations of the five members of NF-B family: p65 (RelA), RelB, c-Rel, p50 and its precursor p105 (NF-B1), p52 and its precursor p100 (NF-B2). There are many comprehensive reviews on the specific aspects of NF-B action (14–24). Here, the features of NF-B signalling initiated by genotoxic agents will be discussed.
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The DNA DSB activated (ATM kinase-dependent) pathway |
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TopIntroductionThe DNA DSB activated...The two-faced PIDDROS-induced NF-{kappa}B...Concluding remarksFundingReferences |
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It is generally acknowledged that creation of DSB initiates signalling by sensor proteins and transducer protein kinase ATM. This kinase forms homodimers in the undamaged cell. Phosphorylation liberates monomers that acquire kinase activity and phosphorylate downstream effector proteins (25
). A plausible scenario is that altered chromatin conformation caused by DSB and other types of damage is detected by ‘molecular sensors’ that initiate a sequence of phosphorylation events and recruitment of repair proteins to the damaged sites. The sensor function resides mainly in the Mre11/Rad50/Nijmegen breakage syndrome (MRN) complex and ATM (26) functionally linked by a feedback loop. ATM alone can respond to alterations in chromatin conformation (25), but in the absence of MRN the activation level is insufficient to evoke an effective response to the damage signal. According to Lee and Paull (26), MRN unwinds the DSB ends, generating single-stranded DNA and thus providing a damage signal followed by ATM dimer dissociation and acquisition of kinase activity. The positive feedback loop becomes functional and both the MRN and ATM activities increase. Subsequently, it was found that some genotoxic agents required ATM to activate the NF-B signalling. Thus, responses to ionizing radiation (27) and CPT (28) are ATM dependent whereas anthracyclines act in an ATM-independent way (29).
As shown in Figure 2, CPT significantly increased the NF-B DNA binding activity in wild type (MRC5CV1) cells whereas this effect was absent in atm–/– (AT5BIVA) cells (Figure 2A, lanes 1–2 and 4–5). Pre-treatment with Pro1, a proteasome inhibitor, abolished the NF-B activation (Figure 2A, lane 6). This suggested the involvement of proteasomal degradation in this ATM-mediated NF-B activation in response to CPT. The activated NF-B was a p50/p65 heterodimer (Figure 2B).
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Activated ATM phosphorylates numerous substrates (30
), including cell cycle checkpoint proteins, members of the DNA repair network and, last but not least, NF-B essential modulator (NEMO). The latter substrate brings us to the NF-B signalling. Essential features of the ATM-dependent signalling system are presented in a simplified way in Figure 3 and described below.
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Apart from ATM activation, DNA damage results, via unknown mechanism, in increased nuclear translocation of two proteins that shuttle between the nuclear and cytoplasmic compartments: p53-inducible death domain-containing protein [PIDD (31
)] and NEMO (also known as IB kinase or IKK
). PIDD forms a complex (PIDDosome) together with receptor-interacting protein 1 (RIP1) (yet another protein imported from the cytoplasm), PIASy and NEMO. PIASy is a protein inhibitor of activated STATy and functions as a small ubiquitin-like modifier (SUMO) ligase which stimulates SUMO-1. These proteins form a complex, in which NEMO becomes transiently sumoylated by SUMO-1, phosphorylated by ATM, mono-ubiquitinated and finally leaves the nucleus complexed with ATM. Thus, upon DNA damage an unknown signal leaves the nucleus and activates a cytoplasmic messenger causing nuclear translocation of PIDD. The nature of the signal is uncertain and it may also be of cytoplasmic origin. ROS are generated in various stress conditions, including genotoxic stress, and were proposed to cause nuclear translocation of NEMO (21,22). Since NEMO lacks the nuclear localization sequence, it may be brought to the nucleus by an unidentified carrier protein (32).
Formation of NEMO/ATM complex, followed by export to the cytoplasm, may be considered a nucleus-to-cytoplasm part of the signalling loop. In a recent report, the nuclear export of NEMO was subsequent to the complex formation with Ran-GTP and presumably with an undefined nuclear export receptor (33). Export of this complex depends on RCC1 (Ran guanine nucleotide exchange factor for Ran GTPase) and calcium. Mutation in RCC1 or calcium chelation blocks NF-B activation (33) (these factors are omitted in Figure 3).
In the cytoplasm, IB kinase (IKK) 
and β molecules bind to NEMO/ATM. An essential component of the complex is also ELKS, a regulatory subunit of IKK, rich in glutamine (E), leucine (L), lysine (K) and serine (S). IKK phosphorylates the IB inhibitor, maintaining the p50/p65 subunits of NF-B sequestered in the cytoplasm. The phosphorylated inhibitor molecules are subsequently ubiquitinated and degraded via the 26S proteasome pathway, liberating NF-B (with the nuclear localization signal unblocked), to act in the cytoplasm-to-nucleus part of the signalling loop. NF-B translocates to the nucleus and functions as transcription factor. Importantly, NF-B can mediate either activation or repression of transcription, depending on phosphorylation, acetylation and association with cofactor proteins (34).
In the diagrams (Figures 3 and 4), ATM is the signal molecule activated by DNA breakage. However, the actual course of events upon a genotoxic impact is more complicated, as the cellular response depends on the character of DNA damage and may involve other players that amplify or support the action of ATM. In some cells exposed to ionizing radiation, the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) is necessary to achieve the full activation of NF-B (35). Panta et al. (36) demonstrated a damage type-specific activation of ATM (by anthracycline doxorubicin) or DNA-PKcs (by N-benzyladriamycin, AD 288, a catalytic inhibitor of topoisomerase II which does not generate DSB). In both cases, the next step is activation of mitogen-activated protein kinase (MAPK)/p90rsk signalling cascade. The ultimate target for phosphorylation is the IKKβ molecule, and the result is NF-B activation. Interestingly, DNA-PKcs may also cause an opposite effect by phosphorylating IKK, thus reducing the DNA binding affinity of NF-B (37). UV radiation does not directly cause DNA strand breakage, but UV-induced NF-B activation is mediated by ATM, PKC 
and p38 MAPK (38). As discussed below, these cell type-dependent variations in substrate choice by kinases such as ATM or DNA-PKcs that are among the earliest responders to DNA damage considerably complicate the overall picture of the NF-B net. For clarity, they are not included in the diagrams (Figures 3 and 4).
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The two-faced PIDD |
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TopIntroductionThe DNA DSB activated...The two-faced PIDDROS-induced NF-{kappa}B...Concluding remarksFundingReferences |
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In the above description of the NF-
B-related signalling in response to DNA damage, PIDD plays a crucial role by enabling recruitment and successive modifications of NEMO (20), but involvement of PIDD does not end there. Depending on the extent of damage (e.g. inflicted by low or high dose of ionizing radiation), autolysis of PIDD produces varying proportions of three types of fragments, two of which, PIDD-C and PIDD-CC (39), determine the choice of the cellular pathway to survival or to apoptotic death (39). Hence, PIDD is often called a molecular switch (22).
This aspect of PIDD function is shown in Figure 4 in the context of the NF-B activating system. PIDD-C is formed after low dose irradiation, i.e. at a relatively low DNA damage level. It translocates to the nucleus (40) and forms a complex with RIP1 and NEMO, as described above. RIP1 is essential for the subsequent events, as well as PIASy, by enabling sumoylation of NEMO. The presence of ATM as a prerequisite for the assembly of this complex has been suggested (41), although according to (20), ATM apparently binds NEMO downstream of the PIDDosome formation. Further downstream events lead to the nuclear translocation of NF-B and activation of transcription of pro-survival genes.
In contrast to PIDD-C, PIDD-CC is produced later in response to heavy DNA damage. PIDD-CC stays in the cytoplasm and recruits RIP-associated I CH-1/ECD3-homologous protein with a death domain (RAIDD) and procaspase 2. The complex (PIDDosome) initiates apoptosis through a mitochondria-dependent pathway (33,42).
ATM generates both pro-survival and pro-apoptotic signals, via the p53 and PIDD–NF-B-dependent pathways, and the ultimate outcome corresponds to the severity of the genotoxic stress and to the specific gene expression profiles of the affected cells (43,44). As mentioned above, PIDD acts as a switch between the pro- and anti-apoptotic signals, in contrast to the simultaneous initiation of the ATM- and p53-dependent pro-apoptotic pathway and pro-survival pathways involving cell cycle checkpoint and DNA repair proteins. The latter are directly or indirectly activated by ATM and marked as repair and recovery proteins in Figure 4. It should be added that p53 contributes to cell cycle regulation and participates in some DNA repair pathways [recent reviews in (45,46)] and also this feature is shown in the diagram.
This duality of pro-apoptotic and pro-survival signals has important consequences for the response of cancer cells to genotoxic stress. As discussed in (43), malignancy is often accompanied by mutations in p53 that leave PIDD–NF-B-dependent signalling as the main ATM-directed signalling pathway. In consequence, after moderate genotoxic impact (decreasing survival by 20–90%), cells with misrepaired DNA damage may retain ability to proliferate. This leads to generation of mutants that would be eliminated in wild-type p53 cell populations by the p53-dependent apoptosis (47). Hence, genetic instability and increased risk of developing cancer may follow.
The pathways presented in Figure 4 are interconnected and remain in an equilibrium that can be shifted at many stages depending on the availability and post-translational modifications of the participating molecules. The final outcome is reflected in cell survival, as shown below in an example taken from Chen et al. (48).
Figure 5 shows how IKKβ deficiency (due to knockout or mutation) affects cytotoxicity of hexavalent chromium [Cr(VI)]. Cr(VI) undergoes intracellular reduction and generates reactive intermediates including ROS, leading to a broad spectrum of DNA damage (49), including S phase-dependent DSB (50) and cell death of the apoptotic or necrotic type. Mouse embryonic fibroblasts derived from wild-type mice and from IKKβ gene knockout mice, and human bronchial epithelial cells, BEAS-2B, transfected with control vector (pCR3), wild-type IKKβ, or kinase-mutated form of IKKβ (IKKβ-KM), were treated with various concentrations of Cr(VI) for 12 h. Cell death was estimated from lactate dehydrogenase release (Figure 5A and B) or clonogenic survival (Figure 5C and D). Inhibition of NF-B activation, caused either by IKKβ gene knockout or by overexpression of IKKβ-KM, resulted in a markedly enhanced cytotoxic effect of Cr(VI) treatment.
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Interestingly, the concept of signalling loop returned in a recent explanation given to the radio adaptation mechanism by Ahmed and Li (17
,18). They proposed that NF-B is a key element of radio adaptation due to the pro-survival signalling, eventually resulting in a decreased radiation sensitivity. Both the ‘classical’ pathway described above and the ‘alternative’ NF-B activation were assumed by Ahmed and Li to contribute to radio adaptation. |
ROS-induced NF-B activation—example of branched linear pathways
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TopIntroductionThe DNA DSB activated...The two-faced PIDDROS-induced NF-{kappa}B...Concluding remarksFundingReferences |
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Some genotoxic agents generate ROS in quantities sufficient to initiate an alternative pathway of NF-
B activation (19,51). ROS also act as modulators of signalling in immune responses, cell death and inflammation, where NF-B is involved. Moreover, the effect of ROS depends on the cellular context; therefore, contradictory experimental observations lead to controversy concerning the role of ROS in NF-B activation (52,53).
Hydrogen peroxide or UV-A (320–400 nm) radiation inflict DNA oxidative lesions due to generation of hydroxyl radicals in Fenton reaction, and at the same time cause considerable damage to cellular membranes. The presence of ROS in the cytoplasmic compartments has important consequences for the signalling system: as previously mentioned, phosphatases are redox regulated and lose catalytic activity after cysteine oxidation. Thus, ROS can shift the balance between phosphorylated (active) and dephosphorylated (inactive) forms of numerous kinases toward active forms. The same effect may be achieved by using okadaic acid, a phosphatase inhibitor (54).
One target kinase thus activated is NIK (NF-B inducing kinase), a member of the MAPK kinase kinase family with a Ser/Thr kinase activity. NIK participates in the induction of NF-B by both TNF and interleukin 1β by phosphorylating IKK (55). Figure 6 shows the main steps of signalling initiated by ROS and leading to NF-B activation. The diagram is highly simplified, since all connections with Jun-N-terminal kinase-mediated pro-apoptotic signalling and feedback loops (24,54,55) were omitted. The report that NF-B p50 subunit is a critical component of the NF-B complexes activated in murine tissues by total body -irradiation (56) is consistent with ROS (products of water radiolysis) generation by ionizing radiation.
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There is also an interesting connection of the presented pathway with the ATM-dependent apoptotic pathway shown in Figure 4. The activated caspase 2 derived from the PIDD–RAIDD–procaspase 2 complex is required for release of cytochrome c (57
). This initiates pro-apoptotic signalling downstream of cytochrome c release which includes caspase 3. The latter caspase cleaves the p75 subunit of complex I of the mitochondrial electron transport chain, resulting in ROS accumulation (58). This observation also may explain the generation of ROS in cells treated with non-oxidating genotoxic agents.
Figure 6 also shows another pathway launched by hydrogen peroxide or UV-B radiation (280–320 nm) [reviewed in (24)]. As before, the key factor is generation of ROS and in consequence inactivation of phosphatases and the resulting activation of casein kinase 2 or tyrosine kinases belonging to the MAPK family. This IKK-independent pathway involves only IB phosphorylation and proteasomal degradation. Different pathways of NF-B activation generate various dimer combinations, and thus the effects of ROS-generating genotoxic factors and agents are tissue specific.
Many functional aspects of the signalling pathways described above remain unknown. To the numerous questions posed by Wu and Miyamoto (21), one can add another concerning the relation between the type of damage inflicted by a given genotoxic agent and the choice of NF-B activation pathway.
Reelfs et al. (59) noted that exposure of skin fibroblasts to UV-A radiation caused an immediate increase in the labile iron pool (LIP) while inducing an increase in the DNA-binding activity of NF-B. The extent of NF-B activation by UV-A correlated with the level of LIP. The latter could be modulated by iron chelators or supplementation with ferric citrate or haemin as a source of iron. These treatments, however, did not affect the basal NF-B DNA-binding activity in unirradiated cells. The same authors noted earlier observations of iron-dependent UV-A-inflicted skin inflammation. To explain the experimental results, they postulated that ‘... (a) the UV-A-induced increase in labile iron is responsible for UV-A-mediated loss of integrity of the nuclear membrane and the consequent transient leakage of proteins between compartments and (b) the UV-A-induced labile iron release plays a role in the UV-A-mediated translocation of NF-B to the nucleus’. This explanation is consistent with the known facts about the cellular effects of UV-A.
Cellular membranes damaged by oxidation include those of lysosomes. These organelles may release iron metalloproteins’ (mainly ferritin) degradation products to the cytosol. The result is an increase in the LIP level and generation of ROS in the Fenton-type reactions (60). The report of Tenopoulou et al. (61) directly connects oxidative stress and the resultant DNA damage and apoptosis with the release of lysosomal redox-active iron into the cytosol. The pathways shown in Figure 6 connect the presence of ROS with activation of NF-B.
It may be concluded that the extent of involvement of various pathways of NF-B activation likely depends on the relative degree of damage inflicted by genotoxic agents in the nuclear and cytoplasmic compartments. UV-A or hydrogen peroxide, while damaging DNA, also causes a considerable oxidative damage within the cytoplasmic compartment. In UV-A or hydrogen peroxide-treated cells, generation of ROS activates the linear pathways shown in Figure 6; as mentioned above, oxidation of cysteine residues in the catalytic sites inactivates phosphatases and thus modulates activity of protein kinases capable of phosphorylating IKK or IB. Damage caused to DNA by a strictly DNA-specific agent like CPT will launch the ATM-dependent signalling loop. X-irradiation activates both the signalling loop—at the lower dose range—and the linear pathways at the higher dose range when the prevailing damage occurs in the cytoplasmic compartment. The ultimate pattern of the cellular response is determined by availability, abundance and localization of proteins participating in signal transduction.
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Concluding remarks |
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TopIntroductionThe DNA DSB activated...The two-faced PIDDROS-induced NF-{kappa}B...Concluding remarksFundingReferences |
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In the last years, a complex panorama of NF-
B activation pathways emerged from the wealth of experimental results. This review concerns only the pathways that function in mammalian cells treated with genotoxic agents. Nevertheless, even this partial picture shows to what extent both the mechanism and outcome of NF-B activation depend on the inducing agent and the cellular context. The intricacy of the NF-B signalling network makes it clear that the apparent possibilities of targeting NF-B signalling in cancer therapy (62–64) must be based on a very detailed understanding of a particular type of cancer and the genetic background of the patient. The tools to this end are available thanks to the new techniques of molecular biology.
A recent paper shows that a rational application of NF-B activation can bring the desired results in animal models. A toll-like receptor-binding drug developed by Burdelya et al. (65) caused NF-B activation and counteracted radiation-induced apoptosis in intestine and bone marrow cells. This prevented or postponed the lethal effect of the X-ray dose used for total body irradiation. The paper shows that a detailed knowledge of NF-B signalling allows to create a rational basis for various therapeutic modes.
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Funding |
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TopIntroductionThe DNA DSB activated...The two-faced PIDDROS-induced NF-{kappa}B...Concluding remarksFundingReferences |
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Ministry of Science and Higher Education (30104031/1298) to K.B.; Ministry of Science and Higher Education for the Institute of Nuclear Chemistry and Technology to I.S.
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Acknowledgments |
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The authors thank Professor Marcin Kruszewski for critical reading of the paper.
Conflict of interest statement: None declared.
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Notes |
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* To whom correspondence should be addressed. Tel: +48 22 504 1226; Fax: +48 22 504 1341; Email: kamil.brzoska{at}ichtj.waw.pl
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References |
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TopIntroductionThe DNA DSB activated...The two-faced PIDDROS-induced NF-{kappa}B...Concluding remarksFundingReferences |
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Received on June 16, 2008; revised on August 23, 2008; accepted on September 2, 2008.
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