PMID- 15790787
OWN - NLM
STAT- MEDLINE
DCOM- 20051128
LR  - 20211203
IS  - 0006-4971 (Print)
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 106
IP  - 7
DP  - 2005 Oct 1
TI  - Differential regulation of the p70 S6 kinase pathway by interferon alpha 
      (IFNalpha) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells.
PG  - 2436-43
AB  - The precise mechanisms by which imatinib mesylate (STI571) and interferon alpha 
      (IFNalpha) exhibit antileukemic effects are not known. We examined the effects of 
      IFNs or imatinib mesylate on signaling pathways regulating initiation of mRNA 
      translation in BCR-ABL-expressing cells. Treatment of IFN-sensitive KT-1 cells 
      with IFNalpha resulted in phosphorylation/activation of mammalian target of 
      rapamycin (mTOR) and downstream activation of p70 S6 kinase. The IFN-activated 
      p70 S6 kinase was found to regulate phosphorylation of S6 ribosomal protein, 
      which regulates translation of mRNAs with oligopyrimidine tracts in the 
      5'-untranslated region. In addition, IFNalpha treatment resulted in an mTOR- 
      and/or phosphatidyl-inositol 3'(PI 3') kinase-dependent phosphorylation of 4E-BP1 
      repressor of mRNA translation on sites that are required for its deactivation and 
      dissociation from the eukaryotic initiation factor-4E (eIF4E) complex. In 
      contrast to the effects of IFNs, imatinib mesylate suppressed p70 S6 kinase 
      activity, consistent with inhibition of BCR-ABL-mediated activation of the 
      mTOR/p70 S6 kinase pathway. Moreover, the mTOR inhibitor rapamycin enhanced the 
      suppressive effects of imatinib mesylate on primary leukemic granulocyte 
      macrophage-colony-forming unit (CFU-GM) progenitors from patients with chronic 
      myelogenous leukemia (CML). Taken altogether, our data demonstrate that IFNs and 
      imatinib mesylate differentially regulate PI 3' kinase/mTOR-dependent signaling 
      cascades in BCR-ABL-transformed cells, consistent with distinct effects of these 
      agents on pathways regulating mRNA translation. They also support the concept 
      that combined use of imatinib mesylate with mTOR inhibitors may be an appropriate 
      future therapeutic strategy for the treatment of CML.
FAU - Parmar, Simrit
AU  - Parmar S
AD  - Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, 
      Northwestern University Medical School, Lakeside Veterans Administration Medical 
      Center, Section of Hematology-Oncology, University of Chicago, IL, USA.
FAU - Smith, Jessica
AU  - Smith J
FAU - Sassano, Antonella
AU  - Sassano A
FAU - Uddin, Shahab
AU  - Uddin S
FAU - Katsoulidis, Efstratios
AU  - Katsoulidis E
FAU - Majchrzak, Beata
AU  - Majchrzak B
FAU - Kambhampati, Suman
AU  - Kambhampati S
FAU - Eklund, Elizabeth A
AU  - Eklund EA
FAU - Tallman, Martin S
AU  - Tallman MS
FAU - Fish, Eleanor N
AU  - Fish EN
FAU - Platanias, Leonidas C
AU  - Platanias LC
LA  - eng
GR  - CA77816/CA/NCI NIH HHS/United States
GR  - CA94079/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050324
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (5' Untranslated Regions)
RN  - 0 (Androstadienes)
RN  - 0 (Benzamides)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Interferon-alpha)
RN  - 0 (Piperazines)
RN  - 0 (Pyrimidines)
RN  - 0 (RNA, Messenger)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - 5' Untranslated Regions
MH  - Androstadienes/pharmacology
MH  - Benzamides
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Gene Expression Regulation, Enzymologic
MH  - *Gene Expression Regulation, Neoplastic
MH  - Granulocytes/cytology/metabolism
MH  - Humans
MH  - Imatinib Mesylate
MH  - Immunoblotting
MH  - Interferon-alpha/*metabolism
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/*enzymology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Piperazines/pharmacology
MH  - Protein Biosynthesis
MH  - Protein Kinases/metabolism
MH  - Pyrimidines/pharmacology
MH  - RNA, Messenger/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*biosynthesis/genetics
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - Stem Cells
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
MH  - Wortmannin
PMC - PMC1895266
EDAT- 2005/03/26 09:00
MHDA- 2005/12/13 09:00
PMCR- 2006/10/01
CRDT- 2005/03/26 09:00
PHST- 2005/03/26 09:00 [pubmed]
PHST- 2005/12/13 09:00 [medline]
PHST- 2005/03/26 09:00 [entrez]
PHST- 2006/10/01 00:00 [pmc-release]
AID - S0006-4971(20)67238-X [pii]
AID - 01062436 [pii]
AID - 10.1182/blood-2004-10-4003 [doi]
PST - ppublish
SO  - Blood. 2005 Oct 1;106(7):2436-43. doi: 10.1182/blood-2004-10-4003. Epub 2005 Mar 
      24.