Document Detail


Ability of the activated PI3K/Akt oncoproteins to synergize with MEK1 and induce cell cycle progression and abrogate the cytokine-dependence of hematopoietic cells.
MedLine Citation:
PMID:  15004527     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Multiple signal transduction pathways, including the Raf/MEK/ERK and PI3K/Akt kinase cascades, play critical roles in transducing growth signals from activated cell surface receptors. Using conditionally and constitutively-active forms of MEK1 and either PI3K or Akt, we demonstrate synergy between these kinases in relieving cytokine-dependence of the FDC-P1 hematopoietic cell line. Cytokine-independent cells were obtained from DeltaMEK1:ER-infected cells at a frequency of 5 x 10(-5) indicating that low frequency of cells expressing beta-estradiol-regulated DeltaMEK1:ER became factor-independent, while activated PI3K or Akt by themselves did not relieve cytokine-dependence. In contrast, cytokine-independent cells were recovered approximately 25 to 250-fold more frequently from DeltaMEK1:ER infected cells also infected with either activated PI3K or Akt. MEK/PI3K and MEK/Akt-responsive cells could be maintained long-term as long as either beta-estradiol or the estrogen receptor antagonist 4-hydroxy-tamoxifen (4HT) were provided. The MEK/PI3K/Akt responsive cells were sensitive to both MEK and PI3K/Akt/p70S6K inhibitors. Synergy was observed when inhibitors which targeted both pathways were added together. These results indicate that there is synergy between the Raf/MEK/ERK and PI3K/Akt pathways in terms of abrogation of cytokine-dependence of hematopoietic cells. Likewise, suppression of multiple signal transduction pathways is a more effective means to inhibit cell cycle progression and induce apoptosis in leukemic cells.
Authors:
John G Shelton; William L Blalock; Edmond R White; Linda S Steelman; James A McCubrey
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2004-04-01
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  3     ISSN:  1538-4101     ISO Abbreviation:  Cell Cycle     Publication Date:  2004 Apr 
Date Detail:
Created Date:  2004-08-04     Completed Date:  2004-09-28     Revised Date:  2013-05-27    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  503-12     Citation Subset:  IM    
Affiliation:
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Annexin A5 / pharmacology
Apoptosis
Cell Cycle
Cell Division
Cell Line
Cell Line, Transformed
Cell Line, Tumor
Cell Membrane / metabolism
Coloring Agents / pharmacology
Cytokines / biosynthesis,  metabolism*
DNA / metabolism
Dose-Response Relationship, Drug
Enzyme Activation
Enzyme Inhibitors / pharmacology
Estradiol / metabolism
Hematopoietic Stem Cells / metabolism*
Interleukin-3 / metabolism
MAP Kinase Kinase 1
Mice
Mitogen-Activated Protein Kinase Kinases / metabolism*
Phosphatidylinositol 3-Kinases / metabolism*
Phosphorylation
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-raf / metabolism
Receptors, Estrogen / antagonists & inhibitors
Retroviridae / genetics
Signal Transduction
Tamoxifen / analogs & derivatives*,  metabolism
Grant Support
ID/Acronym/Agency:
R01CA098195/CA/NCI NIH HHS; R01CA51025/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Annexin A5; 0/Coloring Agents; 0/Cytokines; 0/Enzyme Inhibitors; 0/Interleukin-3; 0/Proto-Oncogene Proteins; 0/Receptors, Estrogen; 10540-29-1/Tamoxifen; 17197F0KYM/afimoxifene; 50-28-2/Estradiol; 9007-49-2/DNA; EC 2.7.1.-/Map2k1 protein, mouse; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/Proto-Oncogene Proteins c-raf; EC 2.7.12.2/MAP Kinase Kinase 1; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases

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