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.

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Author:Khalil Ahmad, Bastian Scholz, Ricardo Capelo, Ilona Schweighöfer, Astrid Stefanie Kahnt, Rolf MarschalekORCiDGND, Dieter SteinhilberORCiDGND
URN:urn:nbn:de:hebis:30:3-418954
URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694866
URL:http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=4703
DOI:https://doi.org/10.18632/oncotarget.4703
ISSN:1949-2553
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/26329759
Parent Title (English):OncoTarget
Publisher:Impact Journals LLC
Place of publication:[S. l.]
Document Type:Article
Language:English
Date of Publication (online):2016/11/10
Date of first Publication:2015/07/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/11/10
Tag:5-lipoxygenase; AF4; HDAC; MLL; calcitriol
Volume:6
Issue:28
Page Number:17
First Page:25784
Last Page:25800
Note:
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
HeBIS-PPN:421384638
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Fachübergreifende Einrichtungen / Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Biochemie, Chemie und Pharmazie
Licence (German):License LogoCreative Commons - Namensnennung 3.0