Cell cycle-dependent phosphorylation of the translational repressor eIF-4E binding protein-1 (4E-BP1)

Heesom, Kate J; Gampel, Alexandra; Mellor, Harry; Denton, Richard M.

doi:10.1016/s0960-9822(01)00422-5

Cited by 118 publications

(125 citation statements)

References 19 publications

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“…However, there are also other candidates for rapamycin-insensitive protein kinase(s) that may phosphorylate Ser 64 and Thr 69 on 4E-BP1 and that could be inhibited by p53. Such enzymes previously implicated in 4E-BP1 phosphorylation include cdc2 (cdk1) (Heesom et al, 2001) andpim-2 (Fox et al, 2003). Although there is no information concerning regulation of the latter, p53 has been shown to downregulate cdc2 expression at the level of transcription (Taylor et al, 1999), and p53-activating stresses such as DNA damage regulate the phosphorylation of cdc2 (Poon et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…One candidate for a rapamycin-insensitive protein kinase that is known to be inhibited by p53 (Ababneh et al, 2001;Taylor and Stark, 2001) and that can also phosphorylate 4E-BP1 (Heesom et al, 2001) is the cyclin-regulated enzyme cdc2 (cdk1). As shown in Figure 8, activation of p53 at the permissive temperature caused both a small decrease (no more than 20%) in the level of this enzyme and a more marked decrease in the extent of phosphorylation of cdc2.…”

Section: P53 Activation and Rapamycin Have Additive Effects On The Inmentioning

confidence: 99%

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Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53

Constantinou

Clemens

2005

Oncogene

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Activation of a temperature-sensitive form of mouse p53 in murine erythroleukaemia cells rapidly inhibits protein synthesis and causes early dephosphorylation and cleavage of protein synthesis initiation factor eIF4GI and the eIF4E-binding protein 4E-BP1. Dephosphorylated 4E-BP1 and the cleaved products of 4E-BP1 and eIF4GI associate with eIF4E under these conditions, concomitant with decreased interaction of full-length eIF4GI with eIF4E. These changes may play an important role in preventing formation of the eIF4F complex and thus the initiation of protein synthesis. As observed previously for eIF4GI, the cleavage of 4E-BP1 is insensitive to the general caspase inhibitor z-VAD.FMK, consistent with a caspase-independent mechanism of factor modification and regulation of protein synthesis. Comparison of the p53-induced patterns of eIF4GI and 4E-BP1 dephosphorylation and cleavage with those caused by the mTOR inhibitor rapamycin indicates that p53 activation and rapamycin have distinct but additive effects. Moreover, p53 activation inhibits rapamycin-insensitive protein kinase activity against 4E-BP1. P53 and rapamycin have additive effects on the inhibition of overall protein synthesis. These data suggest that the inhibition of protein synthesis by p53 is largely independent of the regulation of rapamycin-sensitive mTOR in the system under investigation.

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Section: Discussionmentioning

confidence: 99%

Section: P53 Activation and Rapamycin Have Additive Effects On The Inmentioning

confidence: 99%

Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53

Constantinou

Clemens

2005

Oncogene

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“…The phosphorylation of these residues is thought to prime 4E-BP1 for further phosphorylation events , which are thought to be required to secure its release from eIF-4E Mothe-Satney et al, 2000a, b) The kinases responsible for these phosphorylations have not been clearly defined. However, the ATM kinase (Yang and Kastan, 2000) and cyclin B-cdk1 (Heesom et al, 2001) have been implicated in the phosphorylation of 4E-BP1 under certain conditions.…”

Section: Introductionmentioning

confidence: 99%

Paclitaxel induces the phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 through a Cdk1-dependent mechanism

Greenberg

Zimmer

2005

Oncogene

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Initial chemotherapeutic treatment triggers a stressrelated response, which can lead to an increase in the expression of survival proteins. In this study we examine whether paclitaxel (PTX) alters the expression and/or phosphorylation of the translation initiation proteins, eukaryotic initiation factor 4E (eIF-4E) and 4E-binding protein (4E-BP1), a suppressor of eIF-4E in the dephosphorylated state. We found that PTX induced the hyperphosphorylation of 4E-BP1 in the breast cancer cell line, MDA MB 231, which reduced its association with eIF-4E, but did not alter the expression and phosphorylation of eIF-4E. The hyperphosphorylation of 4E-BP1 correlated with G2/M accumulation and with an increase in the phosphorylation of cdk1 substrates. Cotreatment with a histone deacetylase inhibitor (an indirect inhibitor of cdk activity), purvalanol A and roscovitine (direct cdk inhibitors), and the reduction of cyclin B expression using RNA interference decreased the hyperphosphorylation of 4E-BP1 in PTX treated cells. The hyperphosphorylation of 4E-BP1 by PTX increased the association of eIF-4E with eIF-4G, whereas cotreatment with purvalanol A inhibited the association of eIF-4E with eIF-4G in PTX treated cells. Taken together, our data suggest that PTXincreases the functional level of eIF-4E by promoting the hyperphosphorylation and release of 4E-BP1 through a cdk1-dependent mechanism.

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“…Although phosphorylation of 4E‐BP1 at T37/46 is thought to be dependent on mTORC‐1 activity, S65 and T70 residues are targeted by additional kinases, including cyclin‐dependent kinase 1 (CDK‐1) (Heesom et al, 2001) and ERKs (Herbert et al, 2002). We determined that APP downregulation caused reduced ERKs activation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

Sobol¹,

Galluzzo²,

Liang³

et al. 2015

Journal Cellular Physiology

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Hypoxic non‐small cell lung cancer (NSCLC) is dependent on Notch‐1 signaling for survival. Targeting Notch‐1 by means of γ‐secretase inhibitors (GSI) proved effective in killing hypoxic NSCLC. Post‐mortem analysis of GSI‐treated, NSCLC‐burdened mice suggested enhanced phosphorylation of 4E‐BP1 at threonines 37/46 in hypoxic tumor tissues. In vitro dissection of this phenomenon revealed that Amyloid Precursor Protein (APP) inhibition was responsible for a non‐canonical 4E‐BP1 phosphorylation pattern rearrangement—a process, in part, mediated by APP regulation of the pseudophosphatase Styx. Upon APP depletion we observed modifications of eIF‐4F composition indicating increased recruitment of eIF‐4A to the mRNA cap. This phenomenon was supported by the observation that cells with depleted APP were partially resistant to silvestrol, an antibiotic that interferes with eIF‐4A assembly into eIF‐4F complexes. APP downregulation in dividing human cells increased the rate of global protein synthesis, both cap‐ and IRES‐dependent. Such an increase seemed independent of mTOR inhibition. After administration of Torin‐1, APP downregulation and Mechanistic Target of Rapamycin Complex 1 (mTORC‐1) inhibition affected 4E‐BP1 phosphorylation and global protein synthesis in opposite fashions. Additional investigations indicated that APP operates independently of mTORC‐1. Key phenomena described in this study were reversed by overexpression of the APP C‐terminal domain. The presented data suggest that APP may be a novel regulator of protein synthesis in dividing human cells, both cancerous and primary. Furthermore, APP appears to affect translation initiation using mechanisms seemingly dissimilar to mTORC‐1 regulation of cap‐dependent protein synthesis. J. Cell. Physiol. 230: 1064–1074, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

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Cell cycle-dependent phosphorylation of the translational repressor eIF-4E binding protein-1 (4E-BP1)

Cited by 118 publications

References 19 publications

Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53

Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53

Paclitaxel induces the phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 through a Cdk1-dependent mechanism

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

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