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  4. TGFv/SMAD signalling modulates MLL and MLL-AF4 mediated 5-lipoxygenase promoter activation
 
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2017
Journal Article
Title

TGFv/SMAD signalling modulates MLL and MLL-AF4 mediated 5-lipoxygenase promoter activation

Abstract
5-Lipoxygenase (5-LO) catalyzes the initial two steps of the conversion of arachidonic acid to leukotrienes which represent a group of pro-inflammatory lipid mediators involved in immune defense reactions as well as inflammation, allergy and cancer. Transforming growth factor-v (TGFv) and calcitriol strongly upregulate 5-LO expression during myeloid cell differentiation and MLL-AF4 has been shown to strongly activate the 5-LO promoter. Here, we investigated the role of TGFv/SMAD signalling in 5-LO promoter activation. We identified two functional SMAD binding elements in the proximal part of the 5-LO promoter which significantly induce 5-LO promoter activity via TGFv and SMAD3/4. Since aberrant 5-LO gene expression has been linked with mixed lineage leukemia (MLL) which is characterized by the presence of MLL fusion proteins (e.g. MLL-AF4), we also investigated the influence of TGFv/SMADs on MLL- and MLL-AF4-mediated 5-LO promoter activation. Our data show that induction of 5-LO promoter activity by SMAD3/4 is MLL-dependent and that knockdown of the MLL complex component MEN1 attenuates the SMAD effect. Our data suggest that induction of 5-LO gene expression by TGFv is at least in part due to stimulation of transcript initiation.
Author(s)
Saul, M.J.
Groher, F.
Hegewald, A.B.
Müller-McNicoll, M.
Marschalek, R.
Suess, B.
Steinhilber, D.
Journal
Prostaglandins & other lipid mediators  
DOI
10.1016/j.prostaglandins.2017.07.006
Language
English
Fraunhofer-Institut für Molekularbiologie und Angewandte Oekologie IME  
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