UMF

Harnessing the Ubiquitin-Proteasome System (UPS) to Suppress Tumors' Growth via Manipulating Generation of NF-κB - ROME

Project title: Harnessing the Ubiquitin-Proteasome System (UPS) to Suppress Tumors' Growth via Manipulating Generation of NF-κB

Acronym: ROME

Competition: P4 – Exploratory Research Project (Proiect de cercetare exploratorie - PCE)

Project code: PN-III-P4-ID-PCE-2020-2252

Project duration: 36 months (01/07/2021- 28/06/2024)

Budget (lei): 1.198.032,00

Coordinator: “Iuliu Hațieganu“ University of Medicine and Pharmacy, Cluj-Napoca – RO, Research Center for Advanced Medicine – MedFUTURE

Project Director: Prof. Dr. Aaron Ciechanover

Summary

The ubiquitin-proteasome system consists of ~ 1,500 components and is involved in all cellular processes. Therefore, it is not surprising that aberrations in the system are involved in the pathogenesis of many diseases, especially malignant pathologies. Preliminary data underlying this project led to the identification of a new ubiquitin ligase: KPC1 (RNF123) - ubiquitin ligase E3 involved in ubiquitination and proteasomal processing of the p105 precursor of NF-κB at its active subunit p50, transforming the NF-κB signaling pathway in a powerful tumor suppressor. Subsequent findings suggest that, since p50 does not have a transactivation domain, it must recruit a partner who has not yet been identified to initiate the tumor suppressive cascade. Consequently, current findings demonstrate the need to re-interrogate paradigms such as the oncogenic role of NF-κB in malignant pathologies by investigating new regulatory proteins and the cooperative activity of the immune system in mediating a new antitumor mechanism. Thus, through this project we hope to understand and use to our advantage, a new mechanism with tumor inhibition activity.

Project objectives

The main objective of the project is to comprehensively elucidate the NF-κB signaling pathway and its role in cancer by identifying the mode of action of the tumor suppressor component, KPC1, with a special emphasis on the recruitment and involvement of the immune system and the unidentified partner of p50 in its inhibitory action on cancer. Thus, the specific objectives of the project are:

Objective 1. Dissection of the immune mechanisms that are involved in KPC1/p50-induced tumor suppression

Objective 2. Identify and dissect the mechanism of action of the partner of p50 to the tumor-suppressing activity

Objective 3. Project management, data dissemination and increasement of Romanian research visibility at international level

Project team

Prof. Aaron Ciechanover, PhD
Prof. Cristina Adela Iuga, PhD
Ciprian Tomuleasa, MD, PhD
Diana Gulei, PhD
Maria Ilieș, PhD
Diana Cenariu, PhD
Bobe Petrushev, MD
Andreea Zimta, PhD student
Anca Onaciu, PhD student
Rares Drula, PhD student
Ruxandra Livia Marian, Medical student

Results:

Project Phase 1 - Dissection of immune mechanisms involved in KPC1/p50-induced tumor suppression activity (Part 1)