Summary NF-κB is a key transcriptional regulator involved in inflammation and cell proliferation, survival, and transformation. Several key steps in its activation are mediated by the ubiquitin (Ub) system. One uncharacterized step is limited proteasomal processing of the NF-κB1 precursor p105 to the p50 active subunit. Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. Overexpression of KPC1 inhibits tumor growth likely mediated via excessive generation of p50. Also, overabundance of p50 downregulates p65, suggesting that a p50-p50 homodimer may modulate transcription in place of the tumorigenic p50-p65. Transcript analysis reveals increased expression of genes associated with tumor-suppressive signals. Overall, KPC1 regulation of NF-κB1 processing appears to constitute an important balancing step among the stimulatory and inhibitory activities of the transcription factor in cell growth control.
Bibliographical noteFunding Information:
Research in the laboratory of A.C. is supported by grants from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), the Israel Science Foundation (ISF), the I-CORE Program of the Planning and Budgeting Committee and the ISF (Grant1775/12), the EU Treat PolyQ Network, the Nobel Laureates Invitation Program of Seoul National University, the Deutsch-Israelische Projektkooperation (DIP), and the Program for Targeting Cancer by Modulating Protein Dynamics supported by Albert Sweet (Malibu, CA). We thank Dr. Kazuhiro Iwai (Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan) for providing us with some cDNAs. RNA-seq and mapping to the human genome was done by the Technion Genome Center. B.S. is supported by a fellowship from the Swiss National Science Foundation. Y.T.K. is supported by The Basic Science Research Programs of the National Research Foundation of Korea (NRF-2013R1A2A2A01014170). A.C. is an Israel Cancer Research Fund (ICRF) USA Professor.
© 2015 Elsevier Inc.