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.
Institute of Pharmaceutical Chemistry / ZAFES, Goethe University Frankfurt, Frankfurt, Germany.
Khalil
K
Ahmad
Institute of Pharmaceutical Biology / ZAFES, Goethe University Frankfurt, Frankfurt, Germany.
Bastian
B
Scholz
Institute of Pharmaceutical Chemistry / ZAFES, Goethe University Frankfurt, Frankfurt, Germany.
Ricardo
R
Capelo
Institute of Pharmaceutical Chemistry / ZAFES, Goethe University Frankfurt, Frankfurt, Germany.
Ilona
I
Schweighöfer
Institute of Pharmaceutical Chemistry / ZAFES, Goethe University Frankfurt, Frankfurt, Germany.
Astrid Stefanie
AS
Kahnt
Institute of Pharmaceutical Biology / ZAFES, Goethe University Frankfurt, Frankfurt, Germany.
Rolf
R
Marschalek
Institute of Pharmaceutical Chemistry / ZAFES, Goethe University Frankfurt, Frankfurt, Germany.
Dieter
D
Steinhilber
D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics; D002117:Calcitriol / Q000494:pharmacology*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D057809:HEK293 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008024:Ligands; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism; D061805:Transcription Elongation, Genetic / Q000187:drug effects*; D035602:Transcriptional Elongation Factors; D014162:Transfection
D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; C497422:KMT2A protein, human; D008024:Ligands; C113855:MLL-AF4 fusion protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D035602:Transcriptional Elongation Factors; C579457:VDR protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human; D011495:Histone-Lysine N-Methyltransferase; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D046988:Proteasome Endopeptidase Complex; D002117:Calcitriol
5-lipoxygenase; AF4; HDAC; MLL; calcitriol