Distinct Regulation of Internal Ribosome Entry Site-mediated Translation following Cellular Stress Is Mediated by Apoptotic Fragments of eIF4G Translation Initiation Factor Family Members eIF4GI and p97/DAP5/NAT1

Many cellular stresses lead to the inhibition of protein synthesis. Despite this, some cellular mRNAs are selectively translated under these conditions. It was suggested that the presence of internal ribosome entry site (IRES) sequences in the 5′-untranslated regions allow these mRNAs to be actively translated despite the overall cessation of protein synthesis. Here we tested the hypothesis that the IRES elements of genes that are involved in the control of cell survival are distinctly regulated by cellular stresses. We show that the transient conditions of cellular stress favor the translation of pro-survival IRES, while the severe apoptotic conditions support translation of pro-death IRES elements. Furthermore, activation of pro-death IRES during the etoposide-induced apoptosis is caspase-dependent and correlates with the expression of apoptotic fragments of two members of the eIF4G translation initiation factor family, p97/DAP5/NAT1 and eIF4GI. Our results suggest that the regulation of IRES translation during stress contributes to the fine-tuning of cell fate. Many cellular stresses lead to the inhibition of protein synthesis. Despite this, some cellular mRNAs are selectively translated under these conditions. It was suggested that the presence of internal ribosome entry site (IRES) sequences in the 5′-untranslated regions allow these mRNAs to be actively translated despite the overall cessation of protein synthesis. Here we tested the hypothesis that the IRES elements of genes that are involved in the control of cell survival are distinctly regulated by cellular stresses. We show that the transient conditions of cellular stress favor the translation of pro-survival IRES, while the severe apoptotic conditions support translation of pro-death IRES elements. Furthermore, activation of pro-death IRES during the etoposide-induced apoptosis is caspase-dependent and correlates with the expression of apoptotic fragments of two members of the eIF4G translation initiation factor family, p97/DAP5/NAT1 and eIF4GI. Our results suggest that the regulation of IRES translation during stress contributes to the fine-tuning of cell fate. internal ribosome entry site untranslated region X-linked inhibitor of apoptosis protein Chinese hamster ovary z-Val-Ala-Asp-fluoromethylketon encephalomyocarditis virus galactosidase chloramphenicol acetyltransferase enzyme-linked immunosorbent assay green fluorescent protein analysis of variance Many chemotherapeutic agents and irradiation induce apoptosis in human cancers. Induction of apoptosis leads to the selective cleavage of translation initiation factors that results in an inhibition of cap-dependent protein synthesis (1Clemens M.J. Bushell M. Jeffrey I.W. Pain V.M. Morley S.J. Cell Death Differ. 2000; 7: 603-615Crossref PubMed Scopus (207) Google Scholar). Despite this, resistant tumor cells arise that up-regulate proteins promoting their survival. Therefore, it is critical to identify the proteins and the mechanism promoting their preferential translation. Translational control is a final regulatory step in gene expression. Cellular mRNAs are translated by the so-called ribosome scanning mechanism (2Jackson R.J. Sonenberg N. Hershey J.W.B. Mathews M.B. Translational Control of Gene Expression. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2000: 127-183Google Scholar). This mechanism involves the specific recognition of the 5′-end m7G structure by the cap-binding protein eIF4E. The eIF4E is a part of the larger cap-binding protein complex eIF4F that consists of eIF4A, eIF4G, and eIF4E. The binding of eIF4F to mRNA further recruits other initiation factors as well as the 40 S ribosomal subunit. This complex is then thought to proceed in the 3′ direction until an AUG initiation codon in a favorable context is encountered, and protein synthesis is initiated. A broad range of cellular stresses lead to the inhibition of translation. This is accomplished by (i) the phosphorylation of some initiation factors and/or their regulators (3Brostrom C.O. Brostrom M.A. Prog. Nucleic Acids Res. Mol. Biol. 1998; 58: 79-125Crossref PubMed Scopus (250) Google Scholar) or (ii) by the proteolytic cleavage of several initiation factors (1Clemens M.J. Bushell M. Jeffrey I.W. Pain V.M. Morley S.J. Cell Death Differ. 2000; 7: 603-615Crossref PubMed Scopus (207) Google Scholar). The rapid inhibition of protein synthesis is believed to function as a protective homeostatic mechanism. In this context, it is noteworthy that mRNAs encoding several oncogenes, survival factors, and proteins critically involved in apoptosis are preferentially translated by a poorly understood cap-independent mechanism under conditions of compromised translation initiation (4Holcik M. Sonenberg N. Korneluk R.G. Trends Genet. 2000; 16: 469-473Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). These mRNAs contain IRES1 (internal ribosome entry sequence) elements in their respective 5′-UTR and were shown to be translated during apoptosis (5Holcik M. Lefebvre C.A. Yeh C. Chow T. Korneluk R.G. Nat. Cell Biol. 1999; 1: 190-192Crossref PubMed Scopus (270) Google Scholar, 6Henis-Korenblit S. Strumpf N.L. Goldstaub D. Kimchi A. Mol. Cell. Biol. 2000; 20: 496-506Crossref PubMed Scopus (157) Google Scholar), cell cycle (7Pyronnet S. Pradayrol L. Sonenberg N. Mol. Cell. 2000; 5: 607-616Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar, 8Cornelis S. Bruynooghe Y. Denecker G. Van Huffel S. Tinton S. Beyaert R. Mol. Cell. 2000; 5: 597-605Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar), development (9Creancier L. Mercier P. Prats A.C. Morello D. Mol. Cell. Biol. 2001; 21: 1833-1840Crossref PubMed Scopus (79) Google Scholar), amino acid availability (10Fernandez J. Yaman I. Mishra R. Merrick W.C. Snider M.D. Lamers W.H. Hatzoglou M. J. Biol. Chem. 2001; 276: 12285-12291Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar), and endoplasmic reticulum stress (11Fernandez J. Bode B. Koromilas A. Diehl J.A. Krukovets I. Snider M.D. Hatzoglou M. J. Biol. Chem. 2002; 277: 11780-11787Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Cellular IRES elements are found in a limited but growing number of mRNAs (12Hellen C.U. Sarnow P. Genes Dev. 2001; 15: 1593-1612Crossref PubMed Scopus (806) Google Scholar). Interestingly, they are found preferentially in the mRNAs of genes involved in the control of cellular proliferation, survival, and death (e.g. FGF2 (13Vagner S. Gensac M.C. Maret A. Bayard F. Amalric F. Prats H. Prats A.C. Mol. Cell. Biol. 1995; 15: 35-44Crossref PubMed Scopus (289) Google Scholar), PDGF (14Bernstein J. Sella O., Le, S.Y. Elroy-Stein O. J. Biol. Chem. 1997; 272: 9356-9362Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar), VEGF (15Stein I. Itin A. Einat P. Skaliter R. Grossman Z. Keshet E. Mol. Cell. Biol. 1998; 18: 3112-3119Crossref PubMed Scopus (425) Google Scholar), IGFII (16Teerink H. Voorma H.O. Thomas A.A. Biochim. Biophys. Acta. 1995; 1264: 403-408Crossref PubMed Scopus (54) Google Scholar), c-Myc (17Nanbru C. Lafon I. Audigier S. Gensac M.C. Vagner S. Huez G. Prats A.C. J. Biol. Chem. 1997; 272: 32061-32066Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar), c-Jun (18Sehgal A. Briggs J. Rinehart-Kim J. Basso J. Bos T.J. Oncogene. 2000; 19: 2836-2845Crossref PubMed Scopus (26) Google Scholar), PITSLRE (8Cornelis S. Bruynooghe Y. Denecker G. Van Huffel S. Tinton S. Beyaert R. Mol. Cell. 2000; 5: 597-605Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar)) XIAP (5Holcik M. Lefebvre C.A. Yeh C. Chow T. Korneluk R.G. Nat. Cell Biol. 1999; 1: 190-192Crossref PubMed Scopus (270) Google Scholar), DAP5 (6Henis-Korenblit S. Strumpf N.L. Goldstaub D. Kimchi A. Mol. Cell. Biol. 2000; 20: 496-506Crossref PubMed Scopus (157) Google Scholar), Apaf-1 (19Coldwell M.J. Mitchell S.A. Stoneley M. MacFarlane M. Willis A.E. Oncogene. 2000; 19: 899-905Crossref PubMed Scopus (171) Google Scholar), and bag-1 (20Coldwell M.J. deSchoolmeester M.L. Fraser G.A. Pickering B.M. Packham G. Willis A.E. Oncogene. 2001; 20: 4095-4100Crossref PubMed Scopus (80) Google Scholar). It was therefore suggested that IRES-mediated translation plays a critical role in the regulation of cell fate (4Holcik M. Sonenberg N. Korneluk R.G. Trends Genet. 2000; 16: 469-473Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). It is not clear, however, how cellular IRES facilitate translation or how this translation mechanism is regulated. We have described previously that the IRES element of a key intrinsic inhibitor of apoptosis, XIAP, is actively translated during serum starvation and low dose γ-irradiation (5Holcik M. Lefebvre C.A. Yeh C. Chow T. Korneluk R.G. Nat. Cell Biol. 1999; 1: 190-192Crossref PubMed Scopus (270) Google Scholar, 21Holcik M. Yeh C. Korneluk R.G. Chow T. Oncogene. 2000; 19: 4174-4177Crossref PubMed Scopus (232) Google Scholar). Importantly, the IRES-mediated translation of XIAP is critical for enhanced survival of cells under acute, but transient conditions of cellular stress, thus supporting the notion that IRES-mediated translation regulates cell fate (5Holcik M. Lefebvre C.A. Yeh C. Chow T. Korneluk R.G. Nat. Cell Biol. 1999; 1: 190-192Crossref PubMed Scopus (270) Google Scholar). In this study we wished to investigate the XIAP IRES translation under different cellular stresses. Furthermore, we wished to test the hypothesis that the IRES elements of other cellular mRNAs that are involved in the cell survival are regulated by physiological stress. We demonstrate that XIAP IRES is active in the conditions of transient stress. In addition, we find that while transient cellular stress favors the translation of pro-survival IRES, severe apoptotic conditions support translation of pro-death IRES. Importantly, the activation of Apaf-1 and DAP5 IRES elements during etoposide-induced apoptosis is caspase-dependent and correlates with the expression of apoptotic fragments of eIF4G initiation factor family members eIF4GI and p97/DAP5/NAT1. Human embryonic kidney (293T), human cervical carcinoma (HeLa), human bladder carcinoma (T24), human glioblastoma (SF539), Chinese hamster ovary (CHO), and mouse fibroblast (NIH3T3) cell lines were cultured in standard conditions in Dulbecco's modified Eagle's medium (293T, HeLa, NIH3T3, SF539), F-12 (CHO), or McCoy's 5A (T24) medium supplemented with 10% fetal calf serum, glutamate, and antibiotics. Transient DNA transfections were done using LipofectAMINE Plus (NIH3T3 and T24 cells) or LipofectAMINE 2000 (293T, HeLa, CHO, and SF539 cells) and the protocol provided by the manufacturer (Invitrogen). Briefly, cells were seeded at a density of 3 × 105 cells/ml in six-well plates and were transfected 24 h later in serum-free Opti-MEM medium (Invitrogen) with 2 μg of DNA. The transfection mixture was replaced 3 h later with fresh DMEM supplemented with 10% fetal calf serum (LipofectAMINE Plus) or left on the cells overnight (LipofectAMINE 2000). Cells were collected for analysis 24 h post-transfection. For the cellular stress experiments 293T cells were seeded at a density of 3 × 105 cells/ml in six-well plates coated with poly-d-lysine (5 μg/ml) along with transfection mixture (12 μl of LipofectAMINE 2000 + 2 μg DNA in 500 μl of Opti-MEM per well). 24 h after seeding and transfection the cells were exposed to either anoxia (90% N2, 5% H2, 5% CO2 in a MACS-VA500 microaerophilic work station), heat stress (42 °C), etoposide (200 μm), or zVAD.fmk (100 μm) for indicated time and then collected for analysis. of 293T cells were done as described that μg of was with μg of indicated expression were μg of was in transfection to for transfection The the human XIAP the IRES of and were described previously (5Holcik M. Lefebvre C.A. Yeh C. Chow T. Korneluk R.G. Nat. Cell Biol. 1999; 1: 190-192Crossref PubMed Scopus (270) Google Scholar, M. Korneluk R.G. Mol. Cell. Biol. PubMed Scopus Google Scholar). The other IRES elements were cells using the with DAP5 (6Henis-Korenblit S. Strumpf N.L. Goldstaub D. Kimchi A. Mol. Cell. Biol. 2000; 20: 496-506Crossref PubMed Scopus (157) Google Scholar) J. Sonenberg N. PubMed Scopus Google Scholar) c-Myc M. S.A. Willis A.E. Oncogene. 1998; 16: PubMed Scopus (285) Google Scholar) The fragments were (Invitrogen) and then the region of the (5Holcik M. Lefebvre C.A. Yeh C. Chow T. Korneluk R.G. Nat. Cell Biol. 1999; 1: 190-192Crossref PubMed Scopus (270) Google Scholar). The and the of were by were by the and were by the and the expression (Invitrogen). the of amino M. D. H. M.J. Morley S.J. Cell Death Differ. 2000; 7: PubMed Scopus (79) Google and the of amino M. D. H. M.J. Morley S.J. Cell Death Differ. 2000; 7: PubMed Scopus (79) Google Scholar)) were by cells (Invitrogen) of the respective fragments of eIF4GI the expression (Invitrogen). The for were as the at their for analysis. transfected cells were in and in the and cell were using the protocol provided by the in cell was by the assay S. M. in Scholar), and the were using the and the protocol provided by the The IRES was as a of in experiments in Cells were in in 2 for at by at × for was by protein assay and of protein were by 10% were by using mouse mouse mouse or at the suggested by or were using the was transfected cells with the (Invitrogen) and with of I. were using the and The the Apaf-1 or DAP5 and with of the gene and of the assay analysis was using the assay and the protocol provided by the Briefly, μg of was overnight at with × of specific and then with The were and on a The fragments were by to allow of translation by IRES elements we the previously described that and chloramphenicol acetyltransferase as and (5Holcik M. Lefebvre C.A. Yeh C. Chow T. Korneluk R.G. Nat. Cell Biol. 1999; 1: 190-192Crossref PubMed Scopus (270) Google Scholar). The IRES elements of XIAP, and were and this were transfected 293T and the of translation was the of and c-Myc IRES elements was that of the control IRES element in the In the IRES elements of XIAP and translation at and The of IRES elements in the was and was the as that of the not It suggested that cellular IRES elements specific protein factors for their function E. R. E. S. J. 2001; PubMed Scopus Google Scholar). we low of for and c-Myc IRES have that these factors cell lines and are not or are at low in 293T We therefore transfected the different cell lines In cell lines tested the translation by IRES of and c-Myc was low with and XIAP IRES elements. The was the T24 bladder carcinoma cell the translation of XIAP IRES was In translation of IRES was in this cell in other cell These results suggest that the of cellular IRES elements In the cellular IRES elements were not as in the translation of the as the IRES. translation is cell the availability or of protein factors that are involved in the of IRES translation. It is noteworthy that the cellular IRES elements in this study human mRNAs they were to translation in human as well as cell lines that the mechanism of translation is of IRES elements is cell Human embryonic kidney (293T), human cervical carcinoma (HeLa), human bladder carcinoma (T24), human glioblastoma (SF539), CHO, and mouse fibroblast (NIH3T3) cell lines were transfected with indicated as described under and the cells were collected for analysis 24 h by in and in the and cell were using the protocol provided by the in cell was by the assay S. M. in Scholar), and the were using the and the protocol provided by the The IRES was as a of The of IRES in an was as in The the of experiments in It that IRES-mediated translation is preferentially during cellular stress (4Holcik M. Sonenberg N. Korneluk R.G. Trends Genet. 2000; 16: 469-473Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar), it different regulatory cap-dependent translation. In addition, IRES-mediated translation selective regulation of genes in to cellular stress. we have shown that translation of XIAP IRES is enhanced during serum starvation or low dose γ-irradiation (5Holcik M. Lefebvre C.A. Yeh C. Chow T. Korneluk R.G. Nat. Cell Biol. 1999; 1: 190-192Crossref PubMed Scopus (270) Google Scholar, 21Holcik M. Yeh C. Korneluk R.G. Chow T. Oncogene. 2000; 19: 4174-4177Crossref PubMed Scopus (232) Google Scholar). the IRES of c-Myc was shown to be stress despite overall of protein synthesis T. Mitchell S.A. Willis A.E. J. 2001; PubMed Scopus Google Scholar). further test this transfected 293T cell were to different of cellular stress stress, and and the of translation was for IRES heat stress and anoxia be as transient the of cells with etoposide induce apoptosis and severe conditions of cellular stress. in in the translation by different IRES elements. stress in of IRES translation. In the translation by the IRES of Apaf-1 and DAP5 was The conditions in an of IRES translation that was by or of IRES translation by XIAP and elements was enhanced In translation by the IRES element of Apaf-1 was The of cells with etoposide in the of cell death with of cells at h not Interestingly, the translation by XIAP, and c-Myc IRES elements was while the translation of IRES however, the of Apaf-1 and DAP5 IRES was enhanced h the of This in IRES was to the of cap-dependent as well as of cap-independent translation These results suggest that during transient stress a mechanism that translation of as Apaf-1 while translation of severe apoptotic conditions support translation of pro-death as Apaf-1 and while the translation of XIAP apoptosis Apaf-1 and DAP5 but not cap-dependent were transfected with the indicated and with etoposide (200 μm) or for h as described under and were as described under and are shown per μg of and were as described under and are shown per μg of IRES IRES was as Cells were transfected with the indicated and with etoposide (200 μm) or for h as described under and were as described under and are shown per μg of IRES was as in a We and have suggested previously that proteolytic fragments of the eIF4G family of initiation factors IRES translation of IRES elements the of apoptosis (1Clemens M.J. Bushell M. Jeffrey I.W. Pain V.M. Morley S.J. Cell Death Differ. 2000; 7: 603-615Crossref PubMed Scopus (207) Google Scholar, M. Sonenberg N. Korneluk R.G. Trends Genet. 2000; 16: 469-473Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, S. Sonenberg N. A.C. M. S. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). We wished to test the activation of Apaf-1 and DAP5 IRES elements during etoposide-induced apoptosis be by mechanism. test this hypothesis the 293T cells transfected with either Apaf-1 or DAP5 IRES were with inhibitor zVAD.fmk and then with etoposide for The of cells with inhibitor etoposide-induced cell death not it the of translation of Apaf-1 and DAP5 IRES that the activation of is for the of IRES the cellular mRNAs as we wished to test the enhanced translation of Apaf-1 and DAP5 IRES is in the of transfected cells with etoposide and/or inhibitor in the of Apaf-1 and DAP5 to to with the of apoptosis leads to activation of we wished to the in Apaf-1 and DAP5 IRES be to activation of with of in the or the of the were and control cells this Induction of apoptosis leads to the cleavage eIF4G family members and in translation (6Henis-Korenblit S. Strumpf N.L. Goldstaub D. Kimchi A. Mol. Cell. Biol. 2000; 20: 496-506Crossref PubMed Scopus (157) Google Scholar, M. D. H. M.J. Morley S.J. Cell Death Differ. 2000; 7: PubMed Scopus (79) Google Scholar). It was suggested that the apoptotic fragments of the eIF4G proteins allow preferential translation of mRNAs (1Clemens M.J. Bushell M. Jeffrey I.W. Pain V.M. Morley S.J. Cell Death Differ. 2000; 7: 603-615Crossref PubMed Scopus (207) Google Scholar, M. Sonenberg N. Korneluk R.G. Trends Genet. 2000; 16: 469-473Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, S. Sonenberg N. A.C. M. S. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). the initiation factor p97/DAP5/NAT1 is by to a the translation of IRES thus a (6Henis-Korenblit S. Strumpf N.L. Goldstaub D. Kimchi A. Mol. Cell. Biol. 2000; 20: 496-506Crossref PubMed Scopus (157) Google Scholar). eIF4GI and are by to their to support IRES translation not M. D. H. M.J. Morley S.J. Cell Death Differ. 2000; 7: PubMed Scopus (79) Google Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar, M. M.J. Morley S.J. J. 2000; PubMed Scopus Google Scholar). the cleavage of several fragments that not in the apoptotic cell A. Sonenberg N. Cell Death Differ. 2000; 7: PubMed Scopus Google Scholar), the part of the the region of binding and that translation initiation E. T. 1998; PubMed Scopus (79) Google Scholar) and is with in apoptotic cells M. D. H. M.J. Morley S.J. Cell Death Differ. 2000; 7: PubMed Scopus (79) Google Scholar). Therefore, we wished to test apoptotic fragments of the eIF4G family be for the of cellular IRES Apaf-1 and in 293T cells were with IRES and either p97/DAP5/NAT1 or expression and the of IRES translation was and and We that the of in a in the of Apaf-1 and but not the other IRES elements. The of p97/DAP5/NAT1 on the translation of either IRES element the expression of translation of Apaf-1 and DAP5 IRES while the expression of the of on IRES translation. It be however, that the a on the IRES translation fragments of eIF4G and p97/DAP5/NAT1 Apaf-1 and DAP5 but not cap-dependent μg of DNA per and were as described under and are shown per μg of and were as described under and are shown per μg of IRES IRES was as + + + + + + + + + + 2 μg of DNA per and were as described under and are shown per μg of IRES was as in a In this study we have shown that cellular IRES elements are regulated by different cellular We tested the hypothesis that IRES elements of cellular mRNAs involved in the control of cell survival are regulated by physiological stress. It was that physiological conditions translation of pro-death mRNAs as or c-Myc translation of pro-survival as XIAP and we that different conditions IRES elements. heat stress of IRES elements XIAP, and were to a Apaf-1 or h of anoxia the of XIAP IRES was while the of Apaf-1 and DAP5 IRES were The was the of cells with the This in the in Apaf-1 and DAP5 IRES while XIAP, and c-Myc IRES were Importantly, these results suggest that the cellular IRES elements to and that either regulatory or For Apaf-1 and DAP5 IRES were by heat stress and by the etoposide while other IRES were XIAP and elements were the two IRES by The of the elements IRES elements further further the of regulation of IRES translation during cellular stress, we the etoposide-induced of IRES translation in We found that the activation of Apaf-1 and DAP5 IRES elements is the of cells with inhibitor zVAD.fmk IRES translation we found that this specific activation of Apaf-1 and DAP5 IRES elements with the expression of apoptotic fragments of the eIF4G family of initiation factors p97/DAP5/NAT1 and eIF4GI. This is not that and Furthermore, fragments the of the proteins that with and and are therefore to translation initiation E. T. 1998; PubMed Scopus (79) Google Scholar). Interestingly, however, while and translation of Apaf-1 and DAP5 IRES the was with the of proteins were This that these two apoptotic fragments be involved in the regulation of IRES translation under different cellular It be however, that in the apoptotic fragments of p97/DAP5/NAT1 and eIF4GI were in cells that were not apoptosis and therefore p97/DAP5/NAT1 and eIF4GI. The presence of the proteins have therefore the of the apoptotic fragments on IRES translation. It was suggested previously that the function as a that IRES-mediated translation during the conditions of cellular stress (4Holcik M. Sonenberg N. Korneluk R.G. Trends Genet. 2000; 16: 469-473Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 6Henis-Korenblit S. Strumpf N.L. Goldstaub D. Kimchi A. Mol. Cell. Biol. 2000; 20: 496-506Crossref PubMed Scopus (157) Google Scholar). The suggest that and this however, fragments support translation of IRES that they in the of the cell an study that the translation of XIAP, and DAP5 IRES elements S. G. T. L. G. Kimchi A. S. A. 2002; PubMed Scopus (131) Google Scholar). in we not of of on the translation of XIAP and c-Myc IRES elements. Furthermore, in experiments we and of Apaf-1 and DAP5 IRES, while S. G. T. L. G. Kimchi A. S. A. 2002; PubMed Scopus (131) Google Scholar) and in the of the IRES elements. In addition, results the of S. G. T. L. G. Kimchi A. S. A. 2002; PubMed Scopus (131) Google Scholar) that the of on IRES translation. it is to the for these it is that the of different and/or the of proteins to these in study the in of Apaf-1 and DAP5 IRES elements by etoposide the by of either or This that these two IRES elements are by the apoptotic fragments of eIF4G family of Furthermore, the p97/DAP5/NAT1 is a of apoptosis (6Henis-Korenblit S. Strumpf N.L. Goldstaub D. Kimchi A. Mol. Cell. Biol. 2000; 20: 496-506Crossref PubMed Scopus (157) Google Scholar), and therefore it be to translation of pro-death and but not the pro-survival IRES elements. Our support the hypothesis that IRES-mediated translation the control that cap-dependent translation during the conditions of cellular stress. In addition, conditions of transient cellular stress, as favor translation of pro-survival IRES, as XIAP, while the severe apoptotic conditions in the activation of pro-death IRES of Apaf-1 and the that IRES translation in transient cellular stress to be further results that the apoptotic fragments of eIF4G translation initiation factor family of pro-death IRES elements during apoptotic stress and to the of cell We the members of for We are to Kimchi for the of p97/DAP5/NAT1 and

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