No. 11

Title: Sag/Rbx2-Cullin RING ligase in cancer: from target identification to drug discovery

Speaker: Yi Sun（孙毅）

Institute of Translational Medicine

Zhejiang University School of Medicine

Host：Lin Mei

          Chinese Institutes for Medical Research, Beijing

Time：9:15-10:30 a.m., Nov. 27, 2023 (Monday)

Location: Room 1322, North Tower, Basic Research Building, Capital Medical University (首都医科大学基础科研楼北楼1322会议室)

Abstract：

Cullin-RING ligase (CRL) is the largest family of E3 ubiquitin ligases, consisting of four components: 1) a scaffold protein cullin with 8 family members, 2) an adaptor protein, 3) a substrate-recognizing protein, and 4) a RING protein with two family members, RBX1 or RBX2 (also known as SAG). Upon activation by cullin neddylation, CRLs promote ubiquitylation and degradation of many key regulatory proteins, thus regulating a variety of biological processes, including cell cycle progression, signal transduction, responses to hypoxia, oxidative stress, DNA damage and repair, DNA replication, and tumorigenesis.

SAG/RBX2 is the RING component of CRLs, required for its activity. SAG is overexpressed in a number of human cancers, which is associated with poor survival of patients. We found that Sag deletion remarkably suppressed tumorigenesis in the lung, and pancreas, triggered by Kras^G12D, and in the prostate, triggered by Pten loss, indicating that Sag is an oncogenic cooperating gene. We are actively engaged in drug discovery effort to find small molecule inhibitors that target SAG E3 ligase and neddylation for anticancer application. More details will be presented.

Selected Papers:

1. The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells. J Clin Invest.2023; 133(4):e162434.
2. Neddylation inhibition induces glutamine uptake and metabolism by targeting CRL3^SPOPE3 ligase in cancer cells. Nat Commun. 2022; 13(1):3034.
3. A small molecule inhibitor of the UBE2F-CRL5 axis induces apoptosis and radiosensitization in lung cancer. Signal Transduct Target Ther.2022; 7(1):354.