PMID- 18809972
OWN - NLM
STAT- MEDLINE
DCOM- 20090128
LR  - 20211203
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Linking)
VI  - 29
IP  - 12
DP  - 2008 Dec
TI  - Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle 
      progression and proliferation in prostate cancer cells.
PG  - 2279-88
LID - 10.1093/carcin/bgn221 [doi]
AB  - 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.
FAU - Bianchini, Andrea
AU  - Bianchini A
AD  - Department of Public Health and Cell Biology, University of Rome Tor Vergata, 
      Rome, Italy.
FAU - Loiarro, Maria
AU  - Loiarro M
FAU - Bielli, Pamela
AU  - Bielli P
FAU - Busa, Roberta
AU  - Busa R
FAU - Paronetto, Maria Paola
AU  - Paronetto MP
FAU - Loreni, Fabrizio
AU  - Loreni F
FAU - Geremia, Raffaele
AU  - Geremia R
FAU - Sette, Claudio
AU  - Sette C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080922
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Cation Transport Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.6.1.- (Adenosine Triphosphatases)
RN  - EC 7.2.2.8 (ATP7A protein, human)
RN  - EC 7.2.2.8 (Copper-Transporting ATPases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenosine Triphosphatases/*metabolism
MH  - Biomarkers, Tumor/analysis
MH  - Blotting, Western
MH  - Cation Transport Proteins/*metabolism
MH  - Cell Cycle/drug effects/*physiology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Copper-Transporting ATPases
MH  - Enzyme Inhibitors/pharmacology
MH  - Eukaryotic Initiation Factor-4E/*metabolism
MH  - Humans
MH  - Male
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Phosphorylation
MH  - Polyribosomes/drug effects/physiology
MH  - Prostatic Neoplasms/*metabolism
MH  - Protein Array Analysis
MH  - Protein Biosynthesis/drug effects/*physiology
MH  - Protein Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA, Messenger/analysis
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/drug effects/*physiology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
EDAT- 2008/09/24 09:00
MHDA- 2009/01/29 09:00
CRDT- 2008/09/24 09:00
PHST- 2008/09/24 09:00 [pubmed]
PHST- 2009/01/29 09:00 [medline]
PHST- 2008/09/24 09:00 [entrez]
AID - bgn221 [pii]
AID - 10.1093/carcin/bgn221 [doi]
PST - ppublish
SO  - Carcinogenesis. 2008 Dec;29(12):2279-88. doi: 10.1093/carcin/bgn221. Epub 2008 
      Sep 22.