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. 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 (Kravtsova-Ivantsiv, Yelena et al. “KPC1-mediated ubiquitination and proteasomal processing of NF-κB1 p105 to p50 restricts tumor growth.” Cell vol. 161,2 (2015): 333-47).
The lab of Nobel Laureate Prof. Aaron Ciechanover is developing a method to interfere with tumor progression based on increased levels of the ubiquitin ligase KPC1, using a PROTAC-induced proteolytic targeting approach and a relevant unique amino acid sequence. PROTACs are bi-headed “molecular glues” that bring together an unrelated ubiquitin ligase and a target substrate to a vicinity that enables ubiquitination and degradation/processing of the substrate.
- Novel mechanism of action
Applications and Opportunities
- Cancer therapy
- Treatment of glioblastoma and breast cancer