The prognostic significance of elongation factor eEF1A2 in ovarian cancer

Pinke, Dixie E.; Kalloger, Steve E.; Francetic, Tanja; Huntsman, David G.; Lee, Jonathan M.

doi:10.1016/j.ygyno.2007.11.019

Cited by 53 publications

(51 citation statements)

References 34 publications

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“…(5,36,37) As noted above, overexpression of protein translation factors, for example, eIF4E and eEF1A2, was associated with tumor growth, invasion and metastasis of lung cancer. (10)(11)(12)(13) The present study showed that eEF2 expression correlated with tumor cell growth and poor prognosis in LADC patients as well. However, post-translational modification of eEF2 is sumoylation, whereas that of eIF4E and eEF1A2 is phosphorylation, which is regulated by hypoxia and mTOR response to inhibit global protein synthesis.…”

Section: Discussionsupporting

confidence: 61%

“…(8,9) Their expression correlates with tumor cell growth, invasion, metastasis and hence a poor prognosis in lung, breast, ovarian cancer and acute myeloid leukemia. (10)(11)(12)(13) When screening mouse monoclonal antibody libraries for Kelch repeats, (14) we serendipitously found monoclonal antibodies to eukaryotic elongation factor 2 (eEF2), a 95 kDa protein that catalyzed translocation of peptidyl-tRNA on the ribosome during the elongation phase of translation. (15) However, the effect of eEF2 has not been determined in LADC.…”

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confidence: 99%

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Sumoylation of eukaryotic elongation factor 2 is vital for protein stability and anti‐apoptotic activity in lung adenocarcinoma cells

et al. 2011

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By screening mouse monoclonal antibody libraries for Kelch repeats, we serendipitously identified monoclonal antibodies to eukaryotic elongation factor 2 (eEF2). Interestingly, eEF2 was highly expressed in lung adenocarcinoma (LADC), but not in the neighboring non-tumor lung tissue. Normally, eEF2 is involved in the peptidyl-tRNA translocation during protein synthesis. Overexpression of eEF2 would implicate an association with disease progression of LADC. In the present study, we investigated the prognostic significance of eEF2 in patients with LADC. Expression of eEF2 was detected by immunoblotting, immunohistochemistry and confocal immunofluorescence microscopy. Our results show that patients with high eEF2 expression had a significantly higher incidence of early tumor recurrence (67.8% vs 18.2%, P = 0.016), and a significantly worse prognosis (P < 0.001). In an in vitro study, silencing of eEF2 expression increased mitochondrial elongation, cellular autophagy and cisplatin sensitivity. Moreover, eEF2 was sumoylated in LADC cells, and eEF2 sumoylation correlated with drug resistance. These results suggest that eEF2 is an anti-apoptotic marker in LADC. However, biological function and involvement of eEF2 in the disease progression of LADC require further studies. (Cancer Sci 2011; 102: 1582-1589 H igh metastatic potential and cell growth rate, as well as resistance to irradiation and anticancer chemotherapeutic agents are major characteristics of lung adenocarcinoma (LADC).(1) To determine whether the malignant characteristics correlated with specific gene expression, we had used different methods to screen gene expression profiles, and we identified several genes of interest such as dihydrodiol dehydrogenase, hepatocyte growth factor (HGF), HGF receptor (or c-Met, a product of proto-oncogene c-met), dynamin-related protein 1 (DRP1) and ATPase family, AAA domain containing 3A (ATAD3A).(2-6) Among these genes, the protein level, but not the mRNA level, of ATAD3A was increased when LADC cells were exposed to the hypoxic condition, suggesting that translation efficacy was altered under such circumstance. (6,7) Protein translation factors, for example, eukaryotic protein initiation factor 4E (eIF4E) and protein elongation factor 1A2 (eEF1A2), have been shown to be associated with oncogenesis. (8,9) Their expression correlates with tumor cell growth, invasion, metastasis and hence a poor prognosis in lung, breast, ovarian cancer and acute myeloid leukemia.(10-13) When screening mouse monoclonal antibody libraries for Kelch repeats, (14) we serendipitously found monoclonal antibodies to eukaryotic elongation factor 2 (eEF2), a 95 kDa protein that catalyzed translocation of peptidyl-tRNA on the ribosome during the elongation phase of translation.(15) However, the effect of eEF2 has not been determined in LADC.In this report, we studied eEF2 expression in LADC specimens by immunoblotting and immunohistochemistry. We statistically evaluated the correlation between eEF2 expression and clinicopathological parameters, as w...

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Section: Discussionsupporting

confidence: 61%

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confidence: 99%

Sumoylation of eukaryotic elongation factor 2 is vital for protein stability and anti‐apoptotic activity in lung adenocarcinoma cells

et al. 2011

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“…The ectopic overexpression of eEF1A2 provides mouse fibroblasts (NIH3T3) with oncogenic potential and accelerates the growth of ovarian carcinoma (ES-2) cells as xenografts in nude mice. In addition, the results of tissue microarray for the assessment of eEF1A2 protein abundance in 500 primary ovarian tumors showed high expression levels in about 30% of all primary ovarian tumors (Pinke et al, 2008). In the present study, we demonstrate a novel mechanism whereby p16…”

Section: Introductionsupporting

confidence: 52%

Tumor suppressor p16INK4a inhibits cancer cell growth by down-regulating eEF1A2 through a direct interaction

Lee

Choi²,

Cho

et al. 2013

Journal of Cell Science

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The tumor suppressor p16INK4a protein is a member of the INK4 family of cyclin-dependent kinase (Cdk) inhibitors, which are involved in the regulation of the eukaryotic cell cycle. However, the mechanisms underlying the anti-proliferative effects of p16INK4a have not been fully elucidated. Using yeast two-hybrid screening, we identified the eukaryotic elongation factor (eEF)1A2 as a novel interacting partner of p16INK4a. eEF1A2 is known to function as a putative oncogene in cancers. The p16INK4a protein interacted with all but the D2 (250–327 aa) domain of eEF1A2. Ectopic expression of p16INK4a decreased the expression of eEF1A2 and inhibited cancer cell growth. Furthermore, suppression of protein synthesis by expression of p16INK4a ex vivo was verified by luciferase reporter activity. Microinjection of p16INK4a mRNA into the cytoplasm of Xenopus embryos suppressed the luciferase mRNA translation, whereas the combination of p16INK4a and morpholino-eEF1A2 showed a further reduction in translational activity. We conclude that the interaction of p16INK4a with eEF1A2 and subsequent down-regulation of the expression and function of eEF1A2 is a novel mechanism explaining the anti-proliferative effects of p16INK4a.

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“…It is noteworthy that eEF1A has been shown to induce ubiquitindependent degradation of certain N␣-acetylated proteins (53) that are implicated in cell proliferation, apoptosis, and carcinogenesis (54-56); indeed, both eEF1A2 and JNK have been implicated as important regulators of these cellular processes (18,33,(57)(58)(59). Importantly, eEF1A2 is overexpressed in a variety of tumors, including ovarian and breast cancers (60,61). The latter may have implications for NPS and global ER stress.…”

Section: Discussionmentioning

confidence: 99%

Degradation of Newly Synthesized Polypeptides by Ribosome-Associated RACK1/c-Jun N-Terminal Kinase/Eukaryotic Elongation Factor 1A2 Complex

Gandin

Gutierrez

Brill

et al. 2013

Molecular and Cellular Biology

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dFolding of newly synthesized polypeptides (NSPs) into functional proteins is a highly regulated process. Rigorous quality control ensures that NSPs attain their native fold during or shortly after completion of translation. Nonetheless, signaling pathways that govern the degradation of NSPs in mammals remain elusive. We demonstrate that the stress-induced c-Jun N-terminal kinase (JNK) is recruited to ribosomes by the receptor for activated protein C kinase 1 (RACK1). RACK1 is an integral component of the 40S ribosome and an adaptor for protein kinases. Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome. These findings establish a role for a RACK1/JNK/eEF1A2 complex in the quality control of NSPs in response to stress.

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The prognostic significance of elongation factor eEF1A2 in ovarian cancer

Cited by 53 publications

References 34 publications

Sumoylation of eukaryotic elongation factor 2 is vital for protein stability and anti‐apoptotic activity in lung adenocarcinoma cells

Sumoylation of eukaryotic elongation factor 2 is vital for protein stability and anti‐apoptotic activity in lung adenocarcinoma cells

Tumor suppressor p16INK4a inhibits cancer cell growth by down-regulating eEF1A2 through a direct interaction

Degradation of Newly Synthesized Polypeptides by Ribosome-Associated RACK1/c-Jun N-Terminal Kinase/Eukaryotic Elongation Factor 1A2 Complex

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