Abstract
The JAK-STAT signal transduction cascade participates in various cellular processes, including immune response, cell replication, differentiation and oncogenesis. Here, we report that this cascade is induced in two human myeloid HL-60 leukemia cell variants by the granulocyte differentiation inducer dimethyl sulfoxide (DMSO) and macrophage differentiation inducer phorbol 12-myristate 13-acetate (PMA). DMSO and PMA also induced the expression and catalytic activity of 2'-5' oligoadenylate synthetase (2-5A synthetase), a known interferon (IFN) inducible enzyme. The HL-60 cell variants included HL-205, which is susceptible to DMSO- and PMA-induced differentiation, and HL-525, which is susceptible to DMSO- but not to PMA-induced differentiation. Treatment of HL-205 and HL-525 cells with DMSO and HL-205 cells with PMA-induced JAK1 phosphorylation, JAK1/STAT1 association, formation of STAT1-STAT2 heterodimers, and the binding of the active IFN stimulating growth factor 3 (ISGF3) to the IFN-stimulated response element (ISRE) fragment isolated from the 2-5A synthetase promoter. These events were either reduced or absent in the resistant HL-525 cells treated with PMA. Taken together, our data implicate the above signaling cascade in DMSO- and PMA-induced 2-5A synthetase expression and catalytic activity in the HL-60 cell system.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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2',5'-Oligoadenylate Synthetase / drug effects
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2',5'-Oligoadenylate Synthetase / genetics*
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2',5'-Oligoadenylate Synthetase / metabolism
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Catalysis
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Cell Cycle Proteins / drug effects
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Cell Cycle Proteins / genetics
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins / metabolism*
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Dimethyl Sulfoxide / pharmacology*
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Gene Expression Regulation, Enzymologic
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Genes, bcl-1 / drug effects
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Genes, bcl-1 / genetics
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HL-60 Cells
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Humans
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Janus Kinase 1
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Leukemia, Myeloid / enzymology*
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Leukemia, Myeloid / metabolism
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Protein-Tyrosine Kinases / metabolism*
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STAT1 Transcription Factor
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Tetradecanoylphorbol Acetate / analogs & derivatives*
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Tetradecanoylphorbol Acetate / pharmacology*
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Trans-Activators / metabolism*
Substances
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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Trans-Activators
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phorbolol myristate acetate
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Protein-Tyrosine Kinases
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JAK1 protein, human
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Janus Kinase 1
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2',5'-Oligoadenylate Synthetase
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Tetradecanoylphorbol Acetate
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Dimethyl Sulfoxide