AF4 and AF4-MLL mediate transcriptional elongation of 5-lipoxygenase mRNA by 1, 25-dihydroxyvitamin D3.
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.
Mesh Terms:
Arachidonate 5-Lipoxygenase, Calcitriol, Cyclin-Dependent Kinase 9, DNA-Binding Proteins, Enzyme Induction, HEK293 Cells, HeLa Cells, Histone Deacetylase Inhibitors, Histone-Lysine N-Methyltransferase, Humans, Leukemia, Ligands, Myeloid-Lymphoid Leukemia Protein, Nuclear Proteins, Oncogene Proteins, Fusion, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Binding, Protein Kinase Inhibitors, Proteolysis, RNA Interference, RNA, Messenger, Receptors, Calcitriol, Transcription Elongation, Genetic, Transcriptional Elongation Factors, Transfection
Arachidonate 5-Lipoxygenase, Calcitriol, Cyclin-Dependent Kinase 9, DNA-Binding Proteins, Enzyme Induction, HEK293 Cells, HeLa Cells, Histone Deacetylase Inhibitors, Histone-Lysine N-Methyltransferase, Humans, Leukemia, Ligands, Myeloid-Lymphoid Leukemia Protein, Nuclear Proteins, Oncogene Proteins, Fusion, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Binding, Protein Kinase Inhibitors, Proteolysis, RNA Interference, RNA, Messenger, Receptors, Calcitriol, Transcription Elongation, Genetic, Transcriptional Elongation Factors, Transfection
Oncotarget
Date: Sep. 22, 2015
PubMed ID: 26329759
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