Cell
Volume 161, Issue 2, 9 April 2015, Pages 333-347
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Article
KPC1-Mediated Ubiquitination and Proteasomal Processing of NF-κB1 p105 to p50 Restricts Tumor Growth

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Highlights

  • KPC1 ubiquitinates p105, resulting in its basal and signal-induced cleavage to p50

  • KPC1 inhibits tumor growth via regulation of p50-dependent tumor suppressor genes

  • KPC1 and p50 levels are correlated and are lower in tumors than in normal tissue

  • Excess p50 downregulates p65, possibly lowering tumorigenic levels of p50-p65 NF-κB

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.

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