|Ability of the activated PI3K/Akt oncoproteins to synergize with MEK1 and induce cell cycle progression and abrogate the cytokine-dependence of hematopoietic cells.|
|PMID: 15004527 Owner: NLM Status: MEDLINE|
|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.|
|John G Shelton; William L Blalock; Edmond R White; Linda S Steelman; James A McCubrey|
Related Documents :
|23100157 - Assessment of immunotoxicity and genotoxicity in workers exposed to low concentrations ...
20824647 - The effect of surface topography on early nfκb signaling in macrophages.
24123177 - "reactive" response evaluation of primary human astrocytes after methylmercury exposure.
19147007 - Primary cilia in planar cell polarity regulation of the inner ear.
25371357 - Chemokine signaling in development and disease.
12429947 - Ucn-01 (7-hydroxystauorsporine) blocks pma-induced maturation and reciprocally promotes...
|Type: Journal Article; Research Support, U.S. Gov't, P.H.S. Date: 2004-04-01|
|Title: Cell cycle (Georgetown, Tex.) Volume: 3 ISSN: 1538-4101 ISO Abbreviation: Cell Cycle Publication Date: 2004 Apr|
|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|
|Languages: eng Pagination: 503-12 Citation Subset: IM|
|Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA.|
|APA/MLA Format Download EndNote Download BibTex|
Annexin A5 / pharmacology
Cell Line, Transformed
Cell Line, Tumor
Cell Membrane / metabolism
Coloring Agents / pharmacology
Cytokines / biosynthesis, metabolism*
DNA / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Estradiol / metabolism
Hematopoietic Stem Cells / metabolism*
Interleukin-3 / metabolism
MAP Kinase Kinase 1
Mitogen-Activated Protein Kinase Kinases / metabolism*
Phosphatidylinositol 3-Kinases / metabolism*
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
Tamoxifen / analogs & derivatives*, metabolism
|R01CA098195/CA/NCI NIH HHS; R01CA51025/CA/NCI NIH HHS|
|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 126.96.36.199/Protein-Serine-Threonine Kinases; EC 188.8.131.52/Proto-Oncogene Proteins c-akt; EC 184.108.40.206/Proto-Oncogene Proteins c-raf; EC 220.127.116.11/MAP Kinase Kinase 1; EC 18.104.22.168/Mitogen-Activated Protein Kinase Kinases|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Nucleolar segregation lags behind the rest of the genome and requires Cdc14p activation by the FEAR ...
Next Document: Cancer stem cells persist in many cancer cell lines.