KPC1-mediated ubiquitination and proteasomal processing of nf-κb1 p105 to p50 restricts tumor growth

Yelena Kravtsova-Ivantsiv, Inna Shomer, Victoria Cohen-Kaplan, Berend Snijder, Giulio Superti-Furga, Hedva Gonen, Thomas Sommer, Tamar Ziv, Arie Admon, Inna Naroditsky, Muhammad Jbara, Ashraf Brik, Eli Pikarsky, Yong Tae Kwon, Ilana Doweck, Aaron Ciechanover*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


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.

Original languageAmerican English
Pages (from-to)333-347
Number of pages15
Issue number2
StatePublished - 9 Apr 2015

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© 2015 Elsevier Inc.


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