AF4 and AF4-MLL mediate transcriptional elongation of 5-lipoxygenase mRNA by 1, 25-dihydroxyvitamin D3

Oncotarget
K AhmadD Steinhilber

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.

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Citations

Aug 31, 2017·Archivum Immunologiae Et Therapiae Experimentalis·Ammad Ahmad FarooqiWaleed O Arafat
Feb 26, 2020·The FEBS Journal·Katharina SchlagBernd L Sorg
Aug 19, 2017·Cellular and Molecular Life Sciences : CMLS·Camille Malouf, Katrin Ottersbach
Apr 30, 2020·Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms·Subham BasuDebabrata Biswas

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Methods Mentioned

BETA
transfection
ELISA
Co-IP
immunoprecipitation
PCR
coimmunoprecipitation
FCS
Infrared Imaging

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