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

Prostaglandins Other Lipid Mediat. 2017 Nov;133:60-67. doi: 10.1016/j.prostaglandins.2017.07.006. Epub 2017 Aug 11.


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.

Keywords: 5-Lipoxygenase; Mixed lineage leukemia; Promoter; Transforming growth factor β.

MeSH terms

  • Arachidonate 5-Lipoxygenase / biosynthesis
  • Arachidonate 5-Lipoxygenase / genetics*
  • Base Sequence
  • Binding Sites
  • Enzyme Induction
  • Gene Knockdown Techniques
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Oncogene Proteins, Fusion / metabolism*
  • Promoter Regions, Genetic / genetics*
  • Signal Transduction*
  • Smad Proteins / metabolism*
  • Transforming Growth Factor beta / metabolism*


  • KMT2A protein, human
  • MLL-AF4 fusion protein, human
  • Oncogene Proteins, Fusion
  • Smad Proteins
  • Transforming Growth Factor beta
  • Myeloid-Lymphoid Leukemia Protein
  • Arachidonate 5-Lipoxygenase
  • Histone-Lysine N-Methyltransferase