MilliporeSigma
  • Home
  • Search Results
  • The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase.

The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase.

Cell (2019-08-10)
Viraj R Sanghvi, Josef Leibold, Marco Mina, Prathibha Mohan, Marjan Berishaj, Zhuoning Li, Matthew M Miele, Nathalie Lailler, Chunying Zhao, Elisa de Stanchina, Agnes Viale, Leila Akkari, Scott W Lowe, Giovanni Ciriello, Ronald C Hendrickson, Hans-Guido Wendel
ABSTRACT

The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)-a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Polybrene Infection / Transfection Reagent, A highly efficient method of gene transfer into mammalian cells leveraging infection with retroviral vectors.
Sigma-Aldrich
DL-Buthionine-(S,R)-sulfoximine
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-15, ascites fluid
Sigma-Aldrich
N-[Tris(hydroxymethyl)methyl]acrylamide, contains ≤7% KCl, 93%