PMID- 15634685
OWN - NLM
STAT- MEDLINE
DCOM- 20050421
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 280
IP  - 12
DP  - 2005 Mar 25
TI  - Cyclin D1 and c-myc internal ribosome entry site (IRES)-dependent translation is 
      regulated by AKT activity and enhanced by rapamycin through a p38 MAPK- and 
      ERK-dependent pathway.
PG  - 10964-73
AB  - The macrolide antibiotic rapamycin inhibits the mammalian target of rapamycin 
      protein (mTOR) kinase resulting in the global inhibition of cap-dependent protein 
      synthesis, a blockade in ribosome component biosynthesis, and G1 cell cycle 
      arrest. G1 arrest may occur by inhibiting the protein synthesis of critical 
      factors required for cell cycle progression. Hypersensitivity to mTOR inhibitors 
      has been demonstrated in cells having elevated levels of AKT kinase activity, 
      whereas cells containing quiescent AKT activity are relatively resistant. Our 
      previous data suggest that low AKT activity induces resistance by allowing 
      continued cap-independent protein synthesis of cyclin D1 and c-Myc proteins. In 
      support of this notion, the current study demonstrates that the human cyclin D1 
      mRNA 5' untranslated region contains an internal ribosome entry site (IRES) and 
      that both this IRES and the c-myc IRES are negatively regulated by AKT activity. 
      Furthermore, we show that cyclin D1 and c-myc IRES function is enhanced following 
      exposure to rapamycin and requires both p38 MAPK and RAF/MEK/ERK signaling, as 
      specific inhibitors of these pathways reduce IRES-mediated translation and 
      protein levels under conditions of quiescent AKT activity. Thus, continued 
      IRES-mediated translation initiation may permit cell cycle progression upon mTOR 
      inactivation in cells in which AKT kinase activity is relatively low.
FAU - Shi, Yijiang
AU  - Shi Y
AD  - Department of Research and Development, Veterans Affairs Greater Los Angeles 
      Healthcare System, David Geffen School of Medicine, University of California, Los 
      Angeles, California 91343, USA.
FAU - Sharma, Anushree
AU  - Sharma A
FAU - Wu, Hong
AU  - Wu H
FAU - Lichtenstein, Alan
AU  - Lichtenstein A
FAU - Gera, Joseph
AU  - Gera J
LA  - eng
GR  - CA096920/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050104
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (5' Untranslated Regions)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 136601-57-5 (Cyclin D1)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
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 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - 5' Untranslated Regions/chemistry
MH  - Cell Cycle Proteins/genetics
MH  - Cell Line
MH  - Cyclin D1/*genetics
MH  - Cyclin-Dependent Kinase Inhibitor p27
MH  - Extracellular Signal-Regulated MAP Kinases/*physiology
MH  - *Genes, myc
MH  - Humans
MH  - PTEN Phosphohydrolase
MH  - Phosphoric Monoester Hydrolases/physiology
MH  - *Protein Biosynthesis
MH  - Protein Kinases/physiology
MH  - Protein Serine-Threonine Kinases/*physiology
MH  - Proto-Oncogene Proteins/*physiology
MH  - Proto-Oncogene Proteins c-akt
MH  - Ribosomes/*physiology
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Suppressor Proteins/genetics/physiology
MH  - p38 Mitogen-Activated Protein Kinases/*physiology
EDAT- 2005/01/07 09:00
MHDA- 2005/04/22 09:00
CRDT- 2005/01/07 09:00
PHST- 2005/01/07 09:00 [pubmed]
PHST- 2005/04/22 09:00 [medline]
PHST- 2005/01/07 09:00 [entrez]
AID - S0021-9258(20)80791-1 [pii]
AID - 10.1074/jbc.M407874200 [doi]
PST - ppublish
SO  - J Biol Chem. 2005 Mar 25;280(12):10964-73. doi: 10.1074/jbc.M407874200. Epub 2005 
      Jan 4.