PMID- 18223253
OWN - NLM
STAT- MEDLINE
DCOM- 20080520
LR  - 20220114
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 13
DP  - 2008 Mar 28
TI  - Suppression of programmed cell death 4 (PDCD4) protein expression by 
      BCR-ABL-regulated engagement of the mTOR/p70 S6 kinase pathway.
PG  - 8601-10
LID - 10.1074/jbc.M707934200 [doi]
AB  - There is accumulating evidence that mammalian target of rapamycin 
      (mTOR)-activated pathways play important roles in cell growth and survival of 
      BCR-ABL-transformed cells. We have previously shown that the mTOR/p70 S6 kinase 
      (p70 S6K) pathway is constitutively activated in BCR-ABL transformed cells and 
      that inhibition of BCR-ABL kinase activity by imatinib mesylate abrogates such 
      activation. We now provide evidence for the existence of a novel regulatory 
      mechanism by which BCR-ABL promotes cell proliferation, involving p70 
      S6K-mediated suppression of expression of programmed cell death 4 (PDCD4), a 
      tumor suppressor protein that acts as an inhibitor of cap-dependent translation 
      by blocking the translation initiation factor eIF4A. Our data also establish that 
      second generation BCR-ABL kinase inhibitors block activation of p70 S6K and 
      downstream engagement of the S6 ribosomal protein in BCR-ABL transformed cells. 
      Moreover, PDCD4 protein expression is up-regulated by inhibition of the BCR-ABL 
      kinase in K562 cells and BaF3/BCR-ABL transfectants, suggesting a mechanism for 
      the generation of the proapoptotic effects of such inhibitors. Knockdown of PDCD4 
      expression results in reversal of the suppressive effects of nilotinib and 
      imatinib mesylate on leukemic progenitor colony formation, suggesting an 
      important role for this protein in the generation of antileukemic responses. 
      Altogether, our studies identify a novel mechanism by which BCR-ABL may promote 
      leukemic cell growth, involving sequential engagement of the mTOR/p70 S6K pathway 
      and downstream suppression of PDCD4 expression.
FAU - Carayol, Nathalie
AU  - Carayol N
AD  - Robert H Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, 
      Northwestern University Medical School and Jesse Brown Veterans Affairs Medical 
      Center, Chicago, IL 60611, USA.
FAU - Katsoulidis, Efstratios
AU  - Katsoulidis E
FAU - Sassano, Antonella
AU  - Sassano A
FAU - Altman, Jessica K
AU  - Altman JK
FAU - Druker, Brian J
AU  - Druker BJ
FAU - Platanias, Leonidas C
AU  - Platanias LC
LA  - eng
GR  - CA 100579/CA/NCI NIH HHS/United States
GR  - CA 121192/CA/NCI NIH HHS/United States
GR  - CA 77816/CA/NCI NIH HHS/United States
GR  - CA 94079/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20080126
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (PDCD4 protein, human)
RN  - 0 (Pyrimidines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (RNA-Binding Proteins)
RN  - 1CC1JFE158 (Dactinomycin)
RN  - 98600C0908 (Cycloheximide)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - F41401512X (nilotinib)
SB  - IM
MH  - Animals
MH  - Apoptosis Regulatory Proteins/genetics/*metabolism
MH  - Cell Line
MH  - Cycloheximide/pharmacology
MH  - Dactinomycin/pharmacology
MH  - *Down-Regulation
MH  - Fusion Proteins, bcr-abl/antagonists & inhibitors/genetics/*metabolism
MH  - Humans
MH  - Mice
MH  - Mutation/genetics
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/*metabolism
MH  - Pyrimidines/pharmacology
MH  - RNA, Small Interfering/pharmacology
MH  - RNA-Binding Proteins/genetics/*metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Up-Regulation/drug effects
PMC - PMC2417162
EDAT- 2008/01/29 09:00
MHDA- 2008/05/21 09:00
PMCR- 2009/03/28
CRDT- 2008/01/29 09:00
PHST- 2008/01/29 09:00 [pubmed]
PHST- 2008/05/21 09:00 [medline]
PHST- 2008/01/29 09:00 [entrez]
PHST- 2009/03/28 00:00 [pmc-release]
AID - S0021-9258(20)52817-2 [pii]
AID - 8601 [pii]
AID - 10.1074/jbc.M707934200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Mar 28;283(13):8601-10. doi: 10.1074/jbc.M707934200. Epub 2008 
      Jan 26.