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

 
: Saul, M.J.; Groher, F.; Hegewald, A.B.; Müller-McNicoll, M.; Marschalek, R.; Suess, B.; Steinhilber, D.

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Prostaglandins & other lipid mediators 133 (2017), pp.60-67
ISSN: 2212-196X
ISSN: 1098-8823
English
Journal Article
Fraunhofer IME ()

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-β (TGFβ) 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 TGFβ/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 TGFβ 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 TGFβ/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 TGFβ is at least in part due to stimulation of transcript initiation.

: http://publica.fraunhofer.de/documents/N-541001.html