Abstract
Stromal cell-derived factor-1 (SDF-1/CXCL12) enhances the survival of hematopoietic stem and progenitor cells in synergy with other cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), steel factor, and thrombopoietin (TPO), and both the PI3K/Akt and MAPK pathways have been linked to this survival. To further evaluate intracellular signaling involved in SDF-1/CXCL12 survival effects, we investigated modulation of downstream signaling molecules. The synergistic survival enhancement of SDF-1/CXCL12 plus other cytokines were directly linked to enhanced phosphorylation of p70/85S6K and cAMP responsive element binding protein (CREB), as well as enhanced induction of the Bcl-2 family member Mcl-1. Most prominently, c-Fos, a component of AP1 transcription factor, was synergistically induced by SDF-1/CXCL12 plus other cytokines. These results suggest that SDF-1/CXCL12 enhanced cell survival in synergy with other cytokines involves activation of CREB and induction of Mcl-1 and c-Fos.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Blotting, Western
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Cell Line
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Cell Survival
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Chemokine CXCL12
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Chemokines, CXC / metabolism
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Chemokines, CXC / physiology*
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Cyclic AMP / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cytokines / metabolism
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Enzyme Activation
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
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Humans
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / metabolism
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Neoplasm Proteins / physiology*
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Phosphorylation
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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Proto-Oncogene Proteins c-fos / metabolism*
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Receptors, CXCR4 / metabolism
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Recombinant Proteins / chemistry
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction
Substances
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CXCL12 protein, human
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Chemokine CXCL12
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Chemokines, CXC
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Cyclic AMP Response Element-Binding Protein
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Cytokines
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-fos
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Receptors, CXCR4
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Recombinant Proteins
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Granulocyte-Macrophage Colony-Stimulating Factor
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Cyclic AMP
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Ribosomal Protein S6 Kinases, 70-kDa