PMID- 15021914
OWN - NLM
STAT- MEDLINE
DCOM- 20040806
LR  - 20211203
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 23
IP  - 19
DP  - 2004 Apr 22
TI  - Interleukin-6 activates phosphoinositol-3' kinase in multiple myeloma tumor cells 
      by signaling through RAS-dependent and, separately, through p85-dependent 
      pathways.
PG  - 3368-75
AB  - The IL-6-induced activation of the phosphatidylinositol-3' kinase (PI3-K)/AKT 
      cascade in multiple myeloma (MM) cells is critical for tumor cell proliferation 
      and viability. Since the IL-6 receptor does not contain binding sites for the p85 
      regulatory portion of PI3-K, intermediate molecules must play a role. 
      Coimmunoprecipitation studies in MM cell lines demonstrated the IL-6-induced 
      formation of two independent PI3-K-containing complexes: one containing p21 RAS 
      but not STAT-3 and a second containing STAT-3 but not RAS. Both complexes 
      demonstrated IL-6-induced lipid kinase activity. IL-6 also generated kinase 
      activity in a mutant p110 molecule that could not bind p85. Use of 
      dominant-negative (DN) constructs confirmed the presence of two independent 
      pathways of activation: a DN RAS prevented the IL-6-induced generation of lipid 
      kinase activity in the mutant p110 molecule but had no effect on activity 
      generated in the STAT-3-containing complex. In contrast, a DN p85 prevented the 
      generation of kinase activity in the STAT-3-containing complex but had no effect 
      on activity generated in the p110 molecule. Both DN constructs significantly 
      prevented the IL-6-induced activation of AKT. MM cells expressing activating RAS 
      mutations demonstrated enhanced IL-6-independent growth and constitutive PI3-K 
      activity. These data indicate two potential independent pathways of PI3-K/AKT 
      activation in MM cells: one mediated via signaling through RAS which is 
      independent of p85 and a second mediated via p85 and due to a STAT-3-containing 
      complex.
CI  - Copyright 2004 Nature Publishing Group
FAU - Hsu, Jung-Hsin
AU  - Hsu JH
AD  - Department of Medicine, West LA VA-UCLA Medical Center and Jonsson Comprehensive 
      Cancer Center, UCLA, Los Angeles, CA 90073, USA.
FAU - Shi, Yijiang
AU  - Shi Y
FAU - Frost, Patrick
AU  - Frost P
FAU - Yan, Huajun
AU  - Yan H
FAU - Hoang, Bao
AU  - Hoang B
FAU - Sharma, Sanjai
AU  - Sharma S
FAU - Gera, Joseph
AU  - Gera J
FAU - Lichtenstein, Alan
AU  - Lichtenstein A
LA  - eng
PT  - Journal Article
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Interleukin-6)
RN  - 0 (Protein Subunits)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Trans-Activators)
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 3.6.5.2 (Oncogene Protein p21(ras))
SB  - IM
MH  - Cell Line
MH  - DNA-Binding Proteins/physiology
MH  - Enzyme Activation
MH  - Humans
MH  - Interleukin-6/*pharmacology
MH  - Multiple Myeloma/*enzymology
MH  - Oncogene Protein p21(ras)/*physiology
MH  - Phosphatidylinositol 3-Kinases/chemistry/*metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Protein Subunits
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - STAT3 Transcription Factor
MH  - *Signal Transduction
MH  - Trans-Activators/physiology
EDAT- 2004/03/17 05:00
MHDA- 2004/08/07 05:00
CRDT- 2004/03/17 05:00
PHST- 2004/03/17 05:00 [pubmed]
PHST- 2004/08/07 05:00 [medline]
PHST- 2004/03/17 05:00 [entrez]
AID - 1207459 [pii]
AID - 10.1038/sj.onc.1207459 [doi]
PST - ppublish
SO  - Oncogene. 2004 Apr 22;23(19):3368-75. doi: 10.1038/sj.onc.1207459.