c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors

Klefström, Juha; Kovanen, Panu E.; Somersalo, Kristina; Hueber, Anne-Odile; Littlewood, Trevor D.; Evan, Gérard I.; Greenberg, Arnold H.; Saksela, Eero; Timonen, Tuomo; Alitalo, Kari

doi:10.1038/sj.onc.1202546

Cited by 12 publications

(11 citation statements)

References 44 publications

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“…Therefore, c-myc expression during apoptosis could be required for the transcription of specific cell surface proteins required for phagocyte recognition, and it has been shown elsewhere that RNA synthesis still occurs during late-stage apoptosis (30). In agreement with this, it has been shown previously that c-Myc-overexpressing fibroblasts are more sensitive to the cytotoxic effects of natural killer cell-derived granules, and in coculture experiments natural killer cells were able to efficiently destroy only target cells which overexpressed cMyc (32).…”

Section: Discussionsupporting

confidence: 67%

c-Myc Protein Synthesis Is Initiated from the Internal Ribosome Entry Segment during Apoptosis

Stoneley

Chappell

Jopling

et al. 2000

Molecular and Cellular Biology

203

194

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Recent studies have shown that during apoptosis protein synthesis is inhibited and that this is in part due to the proteolytic cleavage of eukaryotic initiation factor 4G (eIF4G). Initiation of translation can occur either by a cap-dependent mechanism or by internal ribosome entry. The latter mechanism is dependent on a complex structural element located in the 5 untranslated region of the mRNA which is termed an internal ribosome entry segment (IRES). In general, IRES-mediated translation does not require eIF4E or full-length eIF4G. In order to investigate whether cap-dependent and cap-independent translation are reduced during apoptosis, we examined the expression of c-Myc during this process, since we have shown previously that the 5 untranslated region of the c-myc proto-oncogene contains an IRES. c-Myc expression was determined in HeLa cells during apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. We have demonstrated that the c-Myc protein is still expressed when more than 90% of the cells are apoptotic. The presence of the protein in apoptotic cells does not result from either an increase in protein stability or an increase in expression of c-myc mRNA. Furthermore, we show that during apoptosis initiation of c-myc translation occurs by internal ribosome entry. We have investigated the signaling pathways that are involved in this response, and cotransfection with plasmids which harbor either wild-type or constitutively active MKK6, a specific immediate upstream activator of p38 mitogen-activated protein kinase (MAPK), increases IRES-mediated translation. In addition, the c-myc IRES is inhibited by SB203580, a specific inhibitor of p38 MAPK. Our data, therefore, strongly suggest that the initiation of translation via the c-myc IRES during apoptosis is mediated by the p38 MAPK pathway.

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Section: Discussionsupporting

confidence: 67%

c-Myc Protein Synthesis Is Initiated from the Internal Ribosome Entry Segment during Apoptosis

Stoneley

Chappell

Jopling

et al. 2000

Molecular and Cellular Biology

203

194

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“…45). The E1A gene product of adenovirus sensitizes infected cells to NK cell killing (46,47), further supporting the hypothesis discussed above that a role for the E3 complex may be to compensate for the increased sensitivity of infected cells to apoptosis induced by other viral genes. Taken together, these data indicate that the inhibition of TRAIL killing by E3-10.4K/14.5K/6.7K may be critical for adenovirus to evade several host cytotoxic effector mechanisms in vivo.…”

Section: Discussionsupporting

confidence: 57%

Three Adenovirus E3 Proteins Cooperate to Evade Apoptosis by Tumor Necrosis Factor-related Apoptosis-inducing Ligand Receptor-1 and -2

Benedict¹,

Norris²,

Prigozy³

et al. 2001

Journal of Biological Chemistry

119

107

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Adenovirus encodes multiple gene products that regulate proapoptotic cellular responses to viral infection mediated by both the innate and adaptive immune systems. The E3-10.4K and 14.5K gene products are known to modulate the death receptor Fas. In this study, we demonstrate that an additional viral E3 protein, 6.7K, functions in the specific modulation of the two death receptors for tumor necrosis factor-related apoptosisinducing ligand (TRAIL). The 6.7K protein is expressed on the cell surface and forms a complex with the 10.4K and 14.5K proteins, and this complex is sufficient to induce down-modulation of TRAIL receptor-1 and -2 from the cell surface and reverse the sensitivity of infected cells to TRAIL-mediated apoptosis. Down-modulation of TRAIL-R2 by the E3 complex is dependent on the cytoplasmic tail of the receptor, but the death domain alone is not sufficient. These results identify a mechanism for viral modulation of TRAIL receptor-mediated apoptosis and suggest the E3 protein complex has evolved to regulate the signaling of selected cytokine receptors.

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“…It was then suggested that this anti-apoptotic action of NF-kB might be mediated by inducing unknown genes responsible for prevention of cell death (Beg and Baltimore, 1996;Wang et al, 1996). However, it is also noted that some genes that are induced by NF-kB, such as p53, Fas ligand and c-Myc, have been implicated in apoptosis (Klefstrom et al, 1997;Siebenlist et al, 1995). Therefore, anti-apoptotic actions of NF-kB may not necessarily require its transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

NF-κB subunit p65 binds to 53BP2 and inhibits cell death induced by 53BP2

et al. 1999

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Nuclear factor kB (NF-kB) is a transcription factor that controls the expression of many cellular and viral genes. The p65 (RelA) subunit plays a critical role as a transcriptional activator and recent observations have highlighted its role in the control of apoptosis. Here we report that 53BP2, a protein previously identi®ed by interaction with wild type p53 and Bcl-2, also binds to p65 in a yeast two-hybrid system. This speci®c interaction was con®rmed by pull-down assay in vitro and by a mammalian two-hybrid assay in vivo. We observed that full-length 53BP2 fused to GFP had a punctate distribution in cytoplasm, predominantly in perinuclear region whereas the N-terminal 53BP2 localized in cytoplasm and C-terminal 53BP2 localized in the nucleus. Furthermore, we found that overexpression of GFP-53BP2 induced apoptosis in transiently transfected cells. Neither the N-terminal nor the Cterminal of 53BP2 fused to GFP induced cell death. Interestingly, co-transfection with a p65 expression plasmid signi®cantly inhibited 53BP2-induced cell death. The previous ®ndings that 53BP2 bound to p53 and Bcl-2 together with our present observations suggest that 53BP2 may play a central role in the regulation of apoptosis and cell growth.

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c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors

Cited by 12 publications

References 44 publications

c-Myc Protein Synthesis Is Initiated from the Internal Ribosome Entry Segment during Apoptosis

c-Myc Protein Synthesis Is Initiated from the Internal Ribosome Entry Segment during Apoptosis

Three Adenovirus E3 Proteins Cooperate to Evade Apoptosis by Tumor Necrosis Factor-related Apoptosis-inducing Ligand Receptor-1 and -2

NF-κB subunit p65 binds to 53BP2 and inhibits cell death induced by 53BP2

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