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

Saul, Meike J. ; Groher, Florian ; Hegewald, Anett B. ; Müller-McNicoll, Michaela ; Marschalek, Rolf ; Suess, Beatrix ; Steinhilber, Dieter :
TGFβ/SMAD signalling modulates MLL and MLL-AF4 mediated 5-lipoxygenase promoter activation.
In: Prostaglandins & other lipid mediators ePub ahead of Print. ISSN 1098-8823
[Artikel], (2017)

Kurzbeschreibung (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.

Typ des Eintrags: Artikel
Erschienen: 2017
Autor(en): Saul, Meike J. ; Groher, Florian ; Hegewald, Anett B. ; Müller-McNicoll, Michaela ; Marschalek, Rolf ; Suess, Beatrix ; Steinhilber, Dieter
Titel: TGFβ/SMAD signalling modulates MLL and MLL-AF4 mediated 5-lipoxygenase promoter activation.
Sprache: Englisch
Kurzbeschreibung (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.

Titel der Zeitschrift, Zeitung oder Schriftenreihe: Prostaglandins & other lipid mediators
Fachbereich(e)/-gebiet(e): 10 Fachbereich Biologie
10 Fachbereich Biologie > Synthetic Genetic Circuits
Hinterlegungsdatum: 29 Aug 2017 06:18
ID-Nummer: pmid:28803964
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