Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels

Fujimura, Ken; Choi, Sunkyu; Wyse, Meghan; Strnádel, Ján; Wright, Tracy; Klemke, Richard L.

doi:10.1074/jbc.m115.687418

Cited by 69 publications

(85 citation statements)

References 52 publications

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“…In contrast, HCMV infected U373MG-IE1 cells exhibit a higher motility rate, enhancing the defect in the migration caused by the deficiency of each Rho protein. It is worth noting the fact that even in the absence or presence of HCMV, parental and their derivative IE1-knockdown RhoA cells exhibited the lowest motility rate even in this more favorable for the IE1-expressing glioblastoma cells context, providing an additional proof reinforcing the significant role of RhoA to promote cell migration [73,74].…”

Section: Discussionmentioning

confidence: 84%

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

Tseliou

Al‐Qahtani²,

Alarifi

et al. 2016

Cell Physiol Biochem

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Background/Aims: Rho GTPases are crucial regulators of the actin cytoskeleton, membrane trafficking and cell signaling and their importance in cell migration and invasion is well- established. The human cytomegalovirus (HCMV) is a widespread pathogen responsible for generally asymptomatic and persistent infections in healthy people. Recent evidence indicates that HCMV gene products are expressed in over 90% of malignant type glioblastomas (GBM). In addition, the HCMV Immediate Early-1 protein (IE1) is expressed in >90% of tumors analyzed. Methods: RhoA, RhoB and RhoC were individually depleted in U373MG glioblastoma cells as well as U373MG cells stably expressing the HCMV IE1 protein (named U373MG-IE1 cells) shRNA lentivirus vectors. Cell proliferation assays, migration as well as wound-healing assays were performed in uninfected and HCMV-infected cells. Results: The depletion of RhoA, RhoB and RhoC protein resulted in significant alterations in the morphology of the uninfected cells, which were further enhanced by the cytopathic effect caused by HCMV. Furthermore, in the absence or presence of HCMV, the knockdown of RhoB and RhoC proteins decreased the proliferation rate of the parental and the IE1-expressing glioblastoma cells, whereas the knockdown of RhoA protein in the HCMV infected cell lines restored their proliferation rate. In addition, wound healing assays in U373MG cells revealed that depletion of RhoA, RhoB and RhoC differentially reduced their migration rate, even in the presence or the absence of HCMV. Conclusion: Collectively, these data show for the first time a differential implication of Rho GTPases in morphology, proliferation rate and motility of human glioblastoma cells during HCMV infection, further supporting an oncomodulatory role of HCMV depending on the Rho isoforms' state.

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Section: Discussionmentioning

confidence: 84%

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

Tseliou

Al‐Qahtani²,

Alarifi

et al. 2016

Cell Physiol Biochem

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“…We particularly used proteomic analyses which investigated the effect of eIF5A depletion (36,37). Fujimura et al .…”

Section: Resultsmentioning

confidence: 99%

eIF5A facilitates translation termination globally and promotes the elongation of many non polyproline-specific tripeptide sequences

Pelechano

Alepuz

2017

Nucleic Acids Research

164

211

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AbstracteIF5A is an essential protein involved in protein synthesis, cell proliferation and animal development. High eIF5A expression is observed in many tumor types and has been linked to cancer metastasis. Recent studies have shown that eIF5A facilitates the translation elongation of stretches of consecutive prolines. Activated eIF5A binds to the empty E-site of stalled ribosomes, where it is thought to interact with the peptidyl-tRNA situated at the P-site. Here, we report a genome-wide analysis of ribosome stalling in Saccharomyces cerevisiae eIF5A depleted cells using 5Pseq. We confirm that, in the absence of eIF5A, ribosomes stall at proline stretches, and extend previous studies by identifying eIF5A-dependent ribosome pauses at termination and at >200 tripeptide motifs. We show that presence of proline, glycine and charged amino acids at the peptidyl transferase center and at the beginning of the peptide exit tunnel arrest ribosomes in eIF5A-depleted cells. Lack of eIF5A also renders ribosome accumulation at the stop codons. Our data indicate specific protein functional groups under the control of eIF5A, including ER-coupled translation and GTPases in yeast and cytoskeleton organization, collagen metabolism and cell differentiation in humans. Our results support a broad mRNA-specific role of eIF5A in translation and identify the conserved motifs that affect translation elongation from yeast to humans.

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“…In this regard, it is interesting that eIF5A does not regulate global protein synthesis, but rather is specifically recruited to the ribosome to fine tune the production of specific subsets of proteins, including proteins that contain one or more polyproline motifs (6, 7). It has been proposed that eIF5A is upregulated in hyperactive cancer cells due to increased demands for such proteins (1, 5–7). PEAK1 and YAP1 do contain polyproline motifs making them good candidates for regulation by eIF5A using this translational mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…eIF5A (eukaryotic translation initiation factor 5A) is an 18-kDa protein that is highly conserved from archae to humans. eIF5A is indispensible for normal mammalian development, is involved in translation elongation, mRNA transport, and is important for cell-cycle progression and proliferation (3–5). Vertebrates carry two genes that encode two highly homologous eIF5A isoforms, eIF5A1 and eIF5A2, which in humans are 84% identical.…”

Section: Introductionmentioning

confidence: 99%

“…eIF5A1 is ubiquitously expressed in all tissues, whereas eIF5A2 expression is primarily restricted to brain and testis. Although the role that eIF5A proteins play in protein synthesis is not fully understood, emerging evidence indicates that eIF5A does not regulate global protein synthesis, but rather enhances and fine-tunes the production of subsets of proteins crucial for hyper-proliferating cancer cells, which have substantial demands for oncogenic and metabolic proteins (5–7). Increased demands for such proteins may explain why eIF5A expression is increased in several cancers, including glioblastoma, leukemia, liver, colon, lung, cervical, PDAC, and ovarian cancer (4, 8).…”

Section: Introductionmentioning

confidence: 99%

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eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

et al. 2017

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In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment. Although eIF5A-PEAK1 signaling contributes to multiple aggressive cancer cell phenotypes, the downstream signaling processes that mediate these responses are uncharacterized. Through proteomics and informatic analyses of PEAK1-depleted PDAC cells, we defined protein translation, cytoskeleton organization and cell cycle regulatory pathways as major pathways controlled by PEAK1. Biochemical and functional studies revealed that the transcription factors YAP1 and TAZ are key targets of eIF5A-PEAK1 signaling. YAP1/TAZ co-immunoprecipitated with PEAK1. Interfering with eIF5A-PEAK1 signaling in PDAC cells inhibited YAP/TAZ protein expression, decreasing expression of stem cell-associated transcription factors (STF) including Oct4, Nanog, c-Myc and TEAD, thereby decreasing 3D tumor sphere growth. Conversely, amplified eIF5A-PEAK1 signaling increased YAP1/TAZ expression, increasing expression of STF and enhancing 3D tumor sphere growth. Informatic interrogation of mRNA sequence databases revealed upregulation of the eIF5A-PEAK1-YAP1-TEAD signaling module in PDAC patients. Taken together, our findings indicate that eIF5A-PEAK1-YAP signaling contributes to PDAC development by regulating an STF program associated with increased tumorigenicity.

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Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels

Cited by 69 publications

References 52 publications

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

eIF5A facilitates translation termination globally and promotes the elongation of many non polyproline-specific tripeptide sequences

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

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