DNA-damaging agents cause inactivation of translational regulators linked to mTOR signalling

Tee, Andrew R.; Proud, Christopher G.

doi:10.1038/sj.onc.1203622

Cited by 114 publications

(103 citation statements)

References 60 publications

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“…Conversely, physiological stresses that cause dephosphorylation of both eIF4E and 4E-BP1 may result in a decreased level of eIF4E and an increased level of 4E-BP1 due to opposite effects on the turnover of these proteins. Consistent with this, exposure of cells to ionizing radiation or DNAdamaging agents, which causes dephosphorylation of 4E-BP1 (Kumar et al, 2000;Tee and Proud, 2000), increases the stability of the protein (Schneider et al, 2005;Le Bouffant et al, 2006). On the other hand, physiological stresses such as heat shock or cadmium chloride increase the ubiquitination and turnover of eIF4E (Othumpangat et al, 2005a;Murata and Shimotohno, 2006).…”

Section: Phosphorylation Ubiquitination and Stability Of 4e-bp1mentioning

confidence: 67%

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

2007

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The availability of the eukaryotic polypeptide chain initiation factor 4E (eIF4E) for protein synthesis is regulated by the 4E-binding proteins (4E-BPs), which act as inhibitors of cap-dependent mRNA translation. The ability of the 4E-BPs to sequester eIF4E is regulated by reversible phosphorylation at multiple sites. We show here that, in addition, 4E-BP1 is a substrate for polyubiquitination and that some forms of 4E-BP1 are simultaneously polyubiquitinated and phosphorylated. In Jurkat cells inhibition of proteasomal activity by MG132 enhances the level of hypophosphorylated, unmodified 4E-BP1 but only modestly increases the accumulation of high-molecularweight, phosphorylated forms of 4E-BP1. In contrast, inhibition of protein phosphatase activity with calyculin A reduces the level of unmodified 4E-BP1 but strongly enhances the amount of phosphorylated, high-molecularweight 4E-BP1. Turnover measurements in the presence of cycloheximide show that, whereas 4E-BP1 is normally a very stable protein, calyculin A decreases the apparent half-life of the normal-sized protein. Affinity chromatography on m 7 GTP-Sepharose indicates that the larger forms of 4E-BP1 bind very poorly to eIF4E. We suggest that the phosphorylation of 4E-BP1 may play a dual role in the regulation of protein synthesis, both reducing the affinity of 4E-BP1 for eIF4E and promoting the conversion of 4E-BP1 to alternative, polyubiquitinated forms.

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Section: Phosphorylation Ubiquitination and Stability Of 4e-bp1mentioning

confidence: 67%

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

2007

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“…This suggested that some CII signals were dominant over other B cell proviability signals, and led us to examine whether there is a differential requirement of type I and II complex-mediated B cell survival and death, respectively, for DNA or protein synthesis. We used mitomycin C, an agent that blocks DNA replication, but that has also been implicated along with other DNA-binding drugs in blocking protein synthesis by affecting synthesis of key regulators in mRNA translation (24). Purified B cells were stimulated overnight with anti-CD40.…”

Section: Differential Requirement For Dna Replication and Protein Synmentioning

confidence: 99%

The Pathway of Antigen Uptake and Processing Dictates MHC Class II-Mediated B Cell Survival and Activation

Nashar

Drake

2005

The Journal of Immunology

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The influence of the pathway of Ag uptake and processing on MHC class II (CII)-mediated B cell function is unknown. In this study, we investigate in resting and activated (via the BCR or CD40) B cells the biological properties of CII-peptide complexes (CII-peptide) generated by either the BCR-mediated Ag processing (type I complex) or fluid phase Ag processing (type II complex). Compared with type I complex, ligation of type II complex by either specific Ab or the TCR in Ag-presenting assay results in significant decreases in B cell survival rate (50–100%) and expression levels of CII, CD86, and CD54. Loss of B cells following ligation of type II complex occurs in the presence of a comparatively good level of specific CD4+ T cell division, indicating that B cell loss is a late event following T cell stimulation. Comparative analysis of T and B cell conjugates after Ab ligation of type I or II complex reveals decreased efficiency of the latter in forming conjugates. Neither initial differential levels of CII and other studied surface markers, B cell type inherent differences, BCR signaling, T cell proliferation, nor initial density of CII-peptide complexes could explain the T cell-induced B cell loss. We propose that the context in which CII-peptide complexes are present in the membrane following BCR uptake and processing leads to B cell survival. Thus, appropriate targeting of Ag ensures generation of relevant immune responses.

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“…We have previously shown that 4E-BP1 is cleaved during apoptosis induced by DNA-damaging agents. 14 It was therefore of interest to check whether 4E-BP1 was cleaved during apoptosis evoked by staurosporine. The cleaved product of 4E-BP1, indicated as the`D' species, was observed after 12 h of staurosporine-treatment ( Figure 1B).…”

Section: Staurosporine Induces Cell Death In Swiss 3t3 Cells Independmentioning

confidence: 99%

“…DNA-damaging agents inhibited mRNA translation even in the presence of the broad spectrum cellpermeable caspase inhibitor, Z-VAD.FMK, and prior to caspase activation. 14,15 This indicates that such inhibition occurred during the pre-execution stage before the cells were committed to die and does not involve caspases. DNA damaging agents caused inhibition of p70 S6 kinase, 4E-BP1 phosphorylation and eIF4F formation, all of which are linked to mTOR-signalling.…”

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confidence: 99%

Staurosporine inhibits phosphorylation of translational regulators linked to mTOR

Tee

Proud

2001

Cell Death Differ

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Treatment of Swiss 3T3 cells with staurosporine resulted in dephosphorylation of two proteins which play key roles in regulating mRNA translation. This occurred before the execution of apoptosis, assessed by caspase-3 activity. These translation regulators are p70 S6 kinase, which phosphorylates ribosomal protein S6, and eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1), which both lie downstream of the mammalian target of rapamycin (mTOR). This resulted in decreased p70 S6 kinase activity, dephosphorylation of ribosomal protein S6, increased binding of 4E-BP1 to eIF4E and a concomitant decrease in eIF4F complexes. Our data show that staurosporine impairs mTOR signalling in vivo but that this not due to direct inhibition of mTOR or to inhibition of protein kinase C. It is becoming clear that agents which cause apoptosis inactivate mTOR signalling as a common early response prior to the execution of apoptosis, i.e., before caspase activation. Cell Death and Differentiation (2001) 8, 841 ± 849.

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DNA-damaging agents cause inactivation of translational regulators linked to mTOR signalling

Cited by 114 publications

References 60 publications

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

The Pathway of Antigen Uptake and Processing Dictates MHC Class II-Mediated B Cell Survival and Activation

Staurosporine inhibits phosphorylation of translational regulators linked to mTOR

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