Carcinogenesis Advance Access originally published online on September 22, 2008
Carcinogenesis 2008 29(12):2279-2288; doi:10.1093/carcin/bgn221
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Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells
1 Department of Public Health and Cell Biology
2 Department of Biology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
3 Neuroembryology Unit, Fondazione Santa Lucia, Via di Fosso del Fiorano 64, 00143 Rome, Italy
* To whom correspondence should be addressed. Tel: +39 06 72596260; Fax: +39 06 72596268; Email: claudio.sette{at}uniroma2.it
Deregulation of the phosphatidyl inositol trisphosphate kinase/AKT/mammalian target of rapamycin (mTOR) and RAS/mitogen-activated protein kinase (MAPK)/MNK pathways frequently occurs in human prostate carcinomas (PCas) and leads to aberrant modulation of messenger RNA (mRNA) translation. We have investigated the relative contribution of these pathways to translational regulation and proliferation of PCa cells. MNK-dependent phosphorylation of eIF4E is elevated in DU145 cells, which have low basal levels of AKT/mTOR activity due to the expression of the tumor suppressor PTEN. In contrast, eIF4E phosphorylation is low in PC3 and LNCaP cells with mutated PTEN and constitutively active AKT/mTOR pathway, but it can be strongly induced through inhibition of mTOR activity by rapamycin or serum depletion. Remarkably, we found that inhibition of MNKs strongly reduced the polysomal recruitment of terminal oligopyrimidine messenger RNAs (TOP mRNAs), which are known targets of mTOR-dependent translational control. Pull-down assays of the eIF4F complex indicated that translation initiation was differently affected by inhibition of MNKs and mTOR. In addition, concomitant treatment with MNK inhibitor and rapamycin exerted additive effects on polysomal recruitment of TOP mRNAs and protein synthesis. The MNK inhibitor was more effective than rapamycin in blocking proliferation of PTEN-expressing cells, whereas combination of the two inhibitors suppressed cell cycle progression in both cell lines. Microarray analysis showed that MNK affected translation of mRNAs involved in cell cycle progression. Thus, our results indicate that a balance between the activity of the AKT/mTOR and the MAPK/MNK pathway in PCa cells maintains a defined translational level of specific mRNAs required for ribosome biogenesis, cell proliferation and stress response and might confer to these cells the ability to overcome negative insults.
Abbreviations: 4E-BP, eIF4E-binding proteins; FBS, fetal bovine serum; IEG, immediate early gene; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; mTOR, mammalian target of rapamycin; PCa, prostate carcinoma; PCR, polymerase chain reaction; PI3K, phosphatidyl inositol trisphosphate kinase; TOP mRNA, terminal oligopyrimidine messenger RNA
Received July 22, 2008; revised September 5, 2008; accepted September 12, 2008.
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