The eukaryotic initiation factor 4E-binding proteins and apoptosis

Proud, Christopher G.

doi:10.1038/sj.cdd.4401588

Cited by 26 publications

(24 citation statements)

References 73 publications

(82 reference statements)

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“…Elevated levels of eIF4E result in inhibition of apoptosis (Clemens, 2004;Mamane et al, 2004), whereas overexpression of 4E-BP1 is proapoptotic (Li et al, 2002;Proud, 2005). It is therefore of interest that calyculin A is also antiapoptotic (Song and Lavin, 1993).…”

Section: Phosphorylation Ubiquitination and Stability Of 4e-bp1mentioning

confidence: 99%

“…Overexpression of eIF4E is associated with malignant transformation (De Benedetti and Graff, 2004), probably because the factor promotes the synthesis of antiapoptotic proteins (Clemens, 2004;Mamane et al, 2004), and many naturally occurring tumours contain elevated levels of eIF4E. Conversely, enhanced expression of 4E-BP1 can reverse the transformed phenotype and increase the susceptibility of cells to apoptosis (Li et al, 2002;Proud, 2005). In naturally occurring tumours, the level of phosphorylation of 4E-BP1 correlates with tumour stage and prognosis (Castellvi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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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: 99%

Section: Introductionmentioning

confidence: 99%

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

2007

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“…4E-BP1 undergoes caspase-dependent cleavage in apoptotic cells. The cleaved 4E-BP1 binds strongly to eIF4E, fails to become sufficiently phosphorylated and thus inhibits cap-dependent translation (Tee and Proud, 2002;Proud, 2005). Furthermore, a non-phosphorylatable mutant of 4E-BP1 mutant, in which the critical phosphorylation site threonine and serine amino acids were mutated to alanines, sensitizes multiple myeloma cells to dexamethasone-induced apoptosis (Yan et al, 2006).…”

Section: Translation Initiation and Apoptosismentioning

confidence: 99%

“…Furthermore, a non-phosphorylatable mutant of 4E-BP1 mutant, in which the critical phosphorylation site threonine and serine amino acids were mutated to alanines, sensitizes multiple myeloma cells to dexamethasone-induced apoptosis (Yan et al, 2006). It is noteworthy that the mRNAs encoding several protein inhibitors of apoptosis (XIAP, c-IAP1 and BCl-2) and pro-apoptotic proteins (c-Myc, APAF-1) contain internal ribosomal entry sites (IRES), which serve to sustain translation during apoptosis, when cap-dependent expression is suppressed (reviewed in Proud, 2004).…”

Section: Translation Initiation and Apoptosismentioning

confidence: 99%

mTOR, translation initiation and cancer

et al. 2006

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“…Sorafenib induces the UPR independently of MEK1/2-ERK1/2 pathway inactivation. Protein synthesis in eukaryotic cells is primarily controlled at the level of translation initiation (43,52). Furthermore, inhibition of protein synthesis represents one of the cardinal features of the unfolded protein response (UPR), a compensatory cellular defense mechanism which is activated by stresses stemming from the burden of misfolded proteins (61,63).…”

mentioning

confidence: 99%

The Kinase Inhibitor Sorafenib Induces Cell Death through a Process Involving Induction of Endoplasmic Reticulum Stress

Rahmani

Davis

Crabtree

et al. 2007

Molecular and Cellular Biology

224

223

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Sorafenib is a multikinase inhibitor that induces apoptosis in human leukemia and other malignant cells.Recently, we demonstrated that sorafenib diminishes Mcl-1 protein expression by inhibiting translation through a MEK1/2-ERK1/2 signaling-independent mechanism and that this phenomenon plays a key functional role in sorafenib-mediated lethality. Here, we report that inducible expression of constitutively active MEK1 fails to protect cells from sorafenib-mediated lethality, indicating that sorafenib-induced cell death is unrelated to MEK1/2-ERK1/2 pathway inactivation. Notably, treatment with sorafenib induced endoplasmic reticulum (ER) stress in human leukemia cells (U937) manifested by immediate cytosolic-calcium mobilization, GADD153 and GADD34 protein induction, PKR-like ER kinase (PERK) and eukaryotic initiation factor 2␣ (eIF2␣) phosphorylation, XBP1 splicing, and a general reduction in protein synthesis as assessed by [35 S]methionine incorporation. These events were accompanied by pronounced generation of reactive oxygen species through a mechanism dependent upon cytosolic-calcium mobilization and a significant decline in GRP78/Bip protein levels. Interestingly, enforced expression of IRE1␣ markedly reduced sorafenib-mediated apoptosis, whereas knockdown of IRE1␣ or XBP1, disruption of PERK activity, or inhibition of eIF2␣ phosphorylation enhanced sorafenib-mediated lethality. Finally, downregulation of caspase-2 or caspase-4 by small interfering RNA significantly diminished apoptosis induced by sorafenib. Together, these findings demonstrate that ER stress represents a central component of a MEK1/2-ERK1/2-independent cell death program triggered by sorafenib.The discovery that aberrant activation of the Ras-Raf-MEK1/2-ERK1/2 module occurs in a high percentage (30%) of human cancers (12, 42, 48, 57) provided a rationale for attempting to disrupt this pathway as a candidate anticancer strategy. Recently, a number of specific inhibitors designed to interrupt this pathway at the level of Ras, Raf, or MEK1/2 have been developed. Among these, sorafenib, a biaryl urea, also known as BAY 43-9006 or Nexavar, was initially developed as a specific inhibitor of C-Raf and B-Raf. However, subsequent studies revealed that it also inhibits several other tyrosine kinases involved in tumor progression, including VEGFR-2, VEGFR-3, PDGFR-␤, Flt3, c-Kit, and Ret (6, 60). Interestingly, sorafenib has been shown to inhibit mutant (V600E) B-Raf kinase activities in vitro and to diminish MEK/extracellular signal-regulated kinase (ERK) activation in various tumor cell lines, including those harboring mutant Ras or B-Raf (25,56,60). Although this compound has potent activity in preclinical tumor xenograft models against a variety of tumor cell types (60), has shown promising activity in a number of clinical trials, and has recently been approved for the treatment of advanced renal cell carcinoma (51), the mechanism(s) by which it exerts its antitumor activity has not been fully elucidated and is currently the subject of ongoing i...

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The eukaryotic initiation factor 4E-binding proteins and apoptosis

Cited by 26 publications

References 73 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

mTOR, translation initiation and cancer

The Kinase Inhibitor Sorafenib Induces Cell Death through a Process Involving Induction of Endoplasmic Reticulum Stress

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