NF-κB: Regulation by Methylation.
In normal cells exposed to stress, the central transcription factor NF-κB is activated only transiently, to modulate the activation of downstream immune responses. However, in most cancers, NF-κB is abnormally activated constitutively, contributing thus to oncogenesis and tumor progression. Therefore, downregulating NF-κB activity is an important goal of cancer treatment. In order to control NF-κB activity therapeutically, it is helpful to understand the molecular mechanisms that normally govern its activation and how dysregulated NF-κB activity may aid the development of disease. Recent evidence from our laboratories and others indicates that, in addition to various posttranslational modifications of NF-κB that have been observed previously, including phosphorylation, ubiquitination, and acetylation, NF-κB can be methylated reversibly on lysine or arginine residues by histone-modifying enzymes, including lysine and arginine methyl transferases and demethylases. Furthermore, these methylations are required to activate many downstream genes. Interestingly, amplifications and mutations of several such enzymes have been linked to cancer. We propose that some of these mutations may alter the methylation not only of histones but also of NF-κB, making them attractive therapeutic targets.
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana. lut@iupui.edu starkg@ccf.org.
Tao
T
Lu
Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio. lut@iupui.edu starkg@ccf.org.
George R
GR
Stark
D000818:Animals; D001120:Arginine / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology; D014158:Transcription, Genetic
D016328:NF-kappa B; D009363:Neoplasm Proteins; D001120:Arginine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; D008239:Lysine