Molecular Therapy: Nucleic Acids (Dec 2022)

Filamin A pre-mRNA editing modulates vascularization and tumor growth

  • Mamta Jain,
  • Greeshma Manjaly,
  • Kathrin Maly,
  • Margreet R. de Vries,
  • Michael Janisiw,
  • Lisa König,
  • Anne Yaël Nossent,
  • Michael F. Jantsch

Journal volume & issue
Vol. 30
pp. 522 – 534

Abstract

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Adenosine to inosine (A to I) editing is mediated by adenosine deaminases acting on RNA (ADAR) enzymes. Inosines are interpreted as guanosines by the translational machinery. Consequently, A to I editing in mRNAs can lead to their recoding and the formation of proteins not encoded in the genome. Filamin A is an actin-crosslinking protein. A to I editing in the filamin pre-mRNA leads to the exchange of a glutamine to an arginine in a highly interactive domain of the protein. However, the consequences of this editing event are still poorly understood. Here we show, using transgenic mice expressing either constitutively edited or constitutively uneditable filamin A that filamin A editing critically controls angiogenesis in tumors but also in a mouse ischemia model. Hyper-editing reduces angiogenesis, while hypoediting leads to increased angiogenesis, possibly by altering vascular endothelial growth factor receptor 2 (VEGFR2) turnover. Further, FLNA editing of the tumor itself seemingly affects its metastatic potential by changing its interaction with the extracellular matrix. We therefore identify filamin A editing as a critical component for angiogenesis, tumor growth, and metastasis formation.

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