Abstract
The human 5-lipoxygenase (5-LO), encoded by the ALOX5 gene, is the key enzyme in the formation of pro-inflammatory leukotrienes. ALOX5 gene transcription is strongly stimulated by calcitriol (1α, 25-dihydroxyvitamin D3) and TGFβ (transforming growth factor-β). Here, we investigated the influence of MLL (activator of transcript initiation), AF4 (activator of transcriptional elongation) as well as of the leukemogenic fusion proteins MLL-AF4 (ectopic activator of transcript initiation) and AF4-MLL (ectopic activator of transcriptional elongation) on calcitriol/TGFβ-dependent 5-LO transcript elongation. We present evidence that the AF4 complex directly interacts with the vitamin D receptor (VDR) and promotes calcitriol-dependent ALOX5 transcript elongation. Activation of transcript elongation was strongly enhanced by the AF4-MLL fusion protein but was sensitive to Flavopiridol. By contrast, MLL-AF4 displayed no effect on transcriptional elongation. Furthermore, HDAC class I inhibitors inhibited the ectopic effects caused by AF4-MLL on transcriptional elongation, suggesting that HDAC class I inhibitors are potential therapeutics for the treatment of t(4;11)(q21;q23) leukemia.
Keywords:
5-lipoxygenase; AF4; HDAC; MLL; calcitriol.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arachidonate 5-Lipoxygenase / biosynthesis*
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Arachidonate 5-Lipoxygenase / genetics
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Calcitriol / pharmacology*
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Cyclin-Dependent Kinase 9 / antagonists & inhibitors
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Cyclin-Dependent Kinase 9 / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enzyme Induction
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HEK293 Cells
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HeLa Cells
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Histone Deacetylase Inhibitors / pharmacology
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism*
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Humans
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Leukemia / drug therapy
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Leukemia / enzymology*
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Leukemia / genetics
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Ligands
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Promoter Regions, Genetic
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors / pharmacology
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Protein Binding
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Protein Kinase Inhibitors / pharmacology
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Proteolysis
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RNA Interference
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RNA, Messenger / biosynthesis*
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RNA, Messenger / genetics
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Receptors, Calcitriol / agonists
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Receptors, Calcitriol / metabolism
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Transcription Elongation, Genetic / drug effects*
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Transcriptional Elongation Factors
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Transfection
Substances
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DNA-Binding Proteins
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Histone Deacetylase Inhibitors
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KMT2A protein, human
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Ligands
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MLL-AF4 fusion protein, human
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Proteasome Inhibitors
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Protein Kinase Inhibitors
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RNA, Messenger
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Receptors, Calcitriol
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Transcriptional Elongation Factors
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VDR protein, human
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Myeloid-Lymphoid Leukemia Protein
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AFF1 protein, human
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Arachidonate 5-Lipoxygenase
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ALOX5 protein, human
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Histone-Lysine N-Methyltransferase
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CDK9 protein, human
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Cyclin-Dependent Kinase 9
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Proteasome Endopeptidase Complex
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Calcitriol