The tumor suppressor functions of ubiquitin ligase KPC1: from cell cycle control to NF-κB regulator.
Diana GuleiRareș DrulaGabriel GhiaurAnca Dana BuzoianuYelena Kravtsova-IvantsivCiprian Ionut TomuleasaAaron CiechanoverPublished in: Cancer research (2023)
The ubiquitin-proteasome system (UPS) is responsible for up to 90% of intracellular protein degradation. Alterations in UPS are extensively involved in the development and advancement of malignant pathologies. Thus, the components of the UPS can become potential targets for cancer therapeutics. KPC1 is an E3 ubiquitin ligase component of the UPS that regulates key pathways and processes in cancer. KPC1 sustains the ubiquitination of cytoplasmic p27, determining its elimination and transition between cell cycle phases. KPC1 also regulates NF-κB signaling by inducing ubiquitination of p105 to allow subsequent proteasomal processing to the functional form p50. It has been shown that the KPC1-p50 duo is reduced or absent in multiple malignancies and that therapeutic reinforcement of the functional axis can exhibit significant tumor suppressor activity. Here, we highlight the potential role of KPC1 as a tumor-suppressor by fully describing its crucial role in p27 signaling and the canonical NF-κB pathway.