Elongation factor-1 alpha is a selective regulator of growth factor withdrawal and ER stress-induced apoptosis

Talapatra, Sunit; Wagner, John D.; Thompson, Craig B.

doi:10.1038/sj.cdd.4401078

Cited by 92 publications

(80 citation statements)

References 38 publications

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“…In this regard, when overexpressed in interleukin-3-dependent FL5.12 cells, EF-1␣ preserves cell viability in the context of interleukin-3 withdrawal and inhibits apoptosis in response to the ER stressors brefeldin A and thapsigargin (32). Together with our findings, these results support the notion that translational control cooperates with well established transcriptional and post-translational mechanisms to oversee the basic apoptotic machinery.…”

Section: Discussionsupporting

confidence: 86%

Translation Initiation Factor 4E Blocks Endoplasmic Reticulum-mediated Apoptosis

Perlman

Peterson

et al. 2004

Journal of Biological Chemistry

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Eukaryotic translation initiation factor 4E (eIF4E) is the mRNA cap-binding protein required for translation of cellular mRNAs utilizing the 5 cap structure. The rate-limiting factor for mRNA recruitment to ribosomes, eIF4E is a major target for regulation of translation by growth factors, hormones, and other extracellular stimuli. When overexpressed, eIF4E exerts profound effects on cell growth and survival, leading to suppression of oncogene-dependent apoptosis, causing malignant transformation and conferring tumors with multiple drug resistance. We found previously that overexpressed eIF4E interdicts the apoptotic pathway induced by growth factor withdrawal and cytotoxic drugs by selectively activating the expression of Bcl-X L , thus preventing mitochondrial release of cytochrome c. In this study, we examined the impact of ectopic eIF4E expression on apoptosis mediated by the endoplasmic reticulum (ER). Here we show that eIF4E rescued cells from the ER stressors brefeldin A, tunicamycin, thapsigargin, and the Ca 2؉ ionophore A23187. In addition, we found that cells rescued from Ca 2؉ ionophore-triggered apoptosis did not release calcium from their ER nor did they translocate caspase-12 from the ER to the cytoplasm. These data lend strong support to the concept that eIF4E functions as a pleiotropic regulator of cell viability and that integration of critical organelle-mediated checkpoints for apoptosis can be controlled by the capdependent translation apparatus.

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Section: Discussionsupporting

confidence: 86%

Translation Initiation Factor 4E Blocks Endoplasmic Reticulum-mediated Apoptosis

Perlman

Peterson

et al. 2004

Journal of Biological Chemistry

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“…They range from protein synthesis (Thornton et al, 2003), oncogenic transformation (Tatsuka et al, 1992), cell proliferation (Gangwani et al, 1998), transporting mRNA (Liu et al, 2002), bundling of F-actin (Gross and Kinzy, 2007), microtubule dynamics (Moore et al, 1998), conferring susceptibility to cell death induced by palmitate overload (Borradaile et al, 2006) or by hydrogen peroxide (Chen et al, 2000), and also conferring cytoprotection against ER-stress-induced apoptosis (Talapatra et al, 2002). EF1A1 expression is elevated in melanomas and tumors (Thornton et al, 2003) and correlates with metastasis (Taniguchi et al, 1992) and oncogenic transformation (Tatsuka et al, 1992).…”

Section: Functional Coupling Between Dlc1 and Ef1a1mentioning

confidence: 99%

The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration

Zhong

Zhang

Yang

et al. 2009

Journal of Cell Science

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Deleted in liver cancer 1 (DLC1) is a multi-modular Rho-GTPase-activating protein (RhoGAP) and a tumor suppressor. Besides its RhoGAP domain, functions of other domains in DLC1 remain largely unknown. By protein precipitation and mass spectrometry, we identified eukaryotic elongation factor 1A1 (EF1A1) as a novel partner for the sterile alpha motif (SAM) domain of DLC1 but not the SAM domain of DLC2. The solution structure of DLC1 SAM revealed a new monomeric fold with four parallel helices, similar to that of DLC2 SAM but distinct from other SAM domains. Mutating F38, L39 and F40 within a hydrophobic patch retained its overall structure but abolished its interaction with EF1A1 with F38 and L39 forming an indispensable interacting motif. DLC1 SAM did not localize to and was not required for DLC1 to suppress the turnover of focal adhesions. Instead, DLC1 SAM facilitated EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation. Compared with wild-type DLC1, the non-interactive DLC1 mutant is less potent in suppressing cell migration, whereas overexpression of the DLC1 SAM domain alone, but not the non-interactive mutant SAM or DLC2 SAM, greatly enhanced cell migration. This finding reveals a novel contribution of the SAM-EF1A1 interaction as a potentially important GAP-independent modulation of cell migration by DLC1.

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“…Interestingly, EF-1␣ has recently been found to regulate stress-induced apoptosis. Overexpression of EF-1␣ leads to resistance to apoptosis induced by certain genotoxic stress (26). Thus, it appears that the role of EF-1␣ in stabilizing microtubules might antagonize induction of apoptosis after cell exposure to certain genotoxic stresses.…”

mentioning

confidence: 99%

Gadd45a Expression Induces Bim Dissociation from the Cytoskeleton and Translocation to Mitochondria

Tong

Jin

et al. 2005

Molecular and Cellular Biology

102

101

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Gadd45a, a p53-and BRCA1-regulated stress protein, has been implicated in the maintenance of genomic fidelity, probably through its roles in the control of cell cycle checkpoint and apoptosis. However, the mechanism(s) by which Gadd45a is involved in the induction of apoptosis remains unclear. We show here that inducible expression of Gadd45a protein causes dissociation of Bim, a Bcl2 family member, from microtubuleassociated components and translocation to mitochondria. The Bim accumulation in mitochondria enhances interaction of Bim with Bcl-2, relieves Bax from Bcl-2-bound complexes, and subsequently results in release of cytochrome c into the cytoplasm. Suppression of endogenous Bim greatly inhibits Gadd45a induction of apoptosis. Interestingly, Gadd45a interacts with elongation factor 1␣ (EF-1␣), a microtubule-severing protein that plays an important role in maintaining cytoskeletal stability, and inhibits EF-1␣-mediated microtubule bundling, indicating that the interaction of Gadd45a with EF-1␣ disrupts cytoskeletal stability. A mutant form of Gadd45a harboring a deletion of EF-1␣-binding domain fails to inhibit microtubule stability and to induce Bim translocation to mitochondria. Furthermore, coexpression of EF-1␣ antagonizes Gadd45a's property of suppressing cell growth and inducing apoptosis. These findings identify a novel link that connects stress protein Gadd45a to the apoptotic machinery and address the importance of cytoskeletal stability in apoptotic response to DNA damage.

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Elongation factor-1 alpha is a selective regulator of growth factor withdrawal and ER stress-induced apoptosis

Cited by 92 publications

References 38 publications

Translation Initiation Factor 4E Blocks Endoplasmic Reticulum-mediated Apoptosis

Translation Initiation Factor 4E Blocks Endoplasmic Reticulum-mediated Apoptosis

The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration

Gadd45a Expression Induces Bim Dissociation from the Cytoskeleton and Translocation to Mitochondria

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