PMID- 21436840
OWN - NLM
STAT- MEDLINE
DCOM- 20110916
LR  - 20211203
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 25
IP  - 7
DP  - 2011 Jul
TI  - Targeting the translational apparatus to improve leukemia therapy: roles of the 
      PI3K/PTEN/Akt/mTOR pathway.
PG  - 1064-79
LID - 10.1038/leu.2011.46 [doi]
AB  - It has become apparent that regulation of protein translation is an important 
      determinant in controlling cell growth and leukemic transformation. The 
      phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homologue deleted on 
      chromosome ten (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway is often 
      implicated in sensitivity and resistance to therapy. Dysregulated signaling 
      through the PI3K/PTEN/Akt/mTOR pathway is often the result of genetic alterations 
      in critical components in this pathway as well as mutations at upstream growth 
      factor receptors. Furthermore, this pathway is activated by autocrine 
      transformation mechanisms. PTEN is a critical tumor suppressor gene and its 
      dysregulation results in the activation of Akt. PTEN is often mutated, silenced 
      and is often haploinsufficient. The mTOR complex1 (mTORC1) regulates the assembly 
      of the eukaryotic initiation factor4F complex, which is critical for the 
      translation of mRNAs that are important for cell growth, prevention of apoptosis 
      and transformation. These mRNAs have long 5'-untranslated regions that are G+C 
      rich, rendering them difficult to translate. Elevated mTORC1 activity promotes 
      the translation of these mRNAs via the phosphorylation of 4E-BP1. mTORC1 is a 
      target of rapamycin and novel active-site inhibitors that directly target the TOR 
      kinase activity. Although rapamycin and novel rapalogs are usually cytostatic and 
      not cytotoxic for leukemic cells, novel inhibitors that target the kinase 
      activities of PI3K and mTOR may prove more effective for leukemia therapy.
FAU - Martelli, A M
AU  - Martelli AM
AD  - Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato 
      Locomotore, Universita di Bologna, Bologna, Italy.
FAU - Evangelisti, C
AU  - Evangelisti C
FAU - Chappell, W
AU  - Chappell W
FAU - Abrams, S L
AU  - Abrams SL
FAU - Basecke, J
AU  - Basecke J
FAU - Stivala, F
AU  - Stivala F
FAU - Donia, M
AU  - Donia M
FAU - Fagone, P
AU  - Fagone P
FAU - Nicoletti, F
AU  - Nicoletti F
FAU - Libra, M
AU  - Libra M
FAU - Ruvolo, V
AU  - Ruvolo V
FAU - Ruvolo, P
AU  - Ruvolo P
FAU - Kempf, C R
AU  - Kempf CR
FAU - Steelman, L S
AU  - Steelman LS
FAU - McCubrey, J A
AU  - McCubrey JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20110325
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CRTC2 protein, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Apoptosis/drug effects/genetics
MH  - Drug Design
MH  - Drug Resistance, Neoplasm/drug effects/genetics
MH  - Gene Expression Regulation, Leukemic/*drug effects/genetics
MH  - Humans
MH  - Leukemia/*drug therapy/genetics
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - MicroRNAs/genetics
MH  - *Molecular Targeted Therapy
MH  - Multiprotein Complexes/antagonists & inhibitors/drug effects/physiology
MH  - Neoplasm Proteins/antagonists & inhibitors/genetics/*physiology
MH  - Neoplastic Stem Cells/drug effects
MH  - PTEN Phosphohydrolase/antagonists & inhibitors/genetics/*physiology
MH  - Phosphatidylinositol 3-Kinases/genetics/*physiology
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Protein Biosynthesis/*drug effects
MH  - Protein Processing, Post-Translational/drug effects
MH  - Proteins/antagonists & inhibitors/drug effects/physiology
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/genetics/*physiology
MH  - Pseudogenes
MH  - RNA, Messenger/genetics
MH  - RNA, Neoplasm/genetics
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*physiology
MH  - Transcription Factors/antagonists & inhibitors/drug effects/physiology
EDAT- 2011/03/26 06:00
MHDA- 2011/09/17 06:00
CRDT- 2011/03/26 06:00
PHST- 2011/03/26 06:00 [entrez]
PHST- 2011/03/26 06:00 [pubmed]
PHST- 2011/09/17 06:00 [medline]
AID - leu201146 [pii]
AID - 10.1038/leu.2011.46 [doi]
PST - ppublish
SO  - Leukemia. 2011 Jul;25(7):1064-79. doi: 10.1038/leu.2011.46. Epub 2011 Mar 25.