RBCK1, also known as RANBP2-type and C3HC4-type zinc finger-containing 1, is a protein-coding gene. It is a subunit of the linear ubiquitin chain assembly complex and acts as an E3 ubiquitin ligase. It participates in multiple pathways, such as NF-κB signaling in the immune response, and is involved in various biological processes like protein degradation and cell survival regulation. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions [2].

In HFpEF, lovastatin-induced up-regulation of the AP-2α/circRNA-RBCK1 signaling suppresses miR-133a in cardiac endothelial cells, preventing diastolic dysfunction, and this effect is abolished by loss of endothelial AP-2α or circRNA-RBCK1 function [1]. In HCC, both RBCK1 and RNF31 are overexpressed, and RBCK1 promotes HCC metastasis and growth by stabilizing RNF31 [2]. In ccRCC, RBCK1 reduces sensitivity to sunitinib, and its inhibition inactivates the AKT and MAPK signaling pathways [3]. In PDAC, depletion of RBCK1 increases the killing effects of ferroptosis inducer on PDAC cells as RBCK1 confers ferroptosis resistance by facilitating MFN2 degradation [4]. In RCC, depletion of RBCK1 severely affects the in-vivo and in-vitro proliferation of renal cancer cells as RBCK1 promotes p53 degradation via ubiquitination [5]. In CRC, RBCK1 promotes chemoresistance and stemness, and its knockdown enhances chemotherapeutic drug sensitivity in a xenograft model [6].

In summary, RBCK1 plays crucial roles in multiple disease conditions. Through model-based research, especially KO/CKO mouse models, it has been revealed that RBCK1 is involved in processes like cardiac function regulation in HFpEF, cancer cell metastasis, growth, chemoresistance, and cell death resistance in various cancers. Understanding RBCK1's functions provides insights into disease mechanisms and potential therapeutic targets for these diseases.

References:

1. Li, Bin, Bai, Wen-Wu, Guo, Tao, Li, Peng, Wang, Shuang-Xi. 2024. Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1. In Nature communications, 15, 2953. doi:10.1038/s41467-024-47327-z. https://pubmed.ncbi.nlm.nih.gov/38580662/

2. Chen, Xijun, Ye, Qing, Zhao, Wenxiu, Xie, Chengrong, Wang, Xiaomin. 2022. RBCK1 promotes hepatocellular carcinoma metastasis and growth by stabilizing RNF31. In Cell death discovery, 8, 334. doi:10.1038/s41420-022-01126-x. https://pubmed.ncbi.nlm.nih.gov/35869046/

3. Wang, Yapeng, Peng, Mou, Zhong, Yawen, Zhu, Liang, Jin, Xin. 2023. The E3 ligase RBCK1 reduces the sensitivity of ccRCC to sunitinib through the ANKRD35-MITD1-ANXA1 axis. In Oncogene, 42, 952-966. doi:10.1038/s41388-023-02613-w. https://pubmed.ncbi.nlm.nih.gov/36732658/

4. Su, Dan, Ding, Chen, Wang, Ruobing, Yang, Gang, Zhang, Taiping. 2024. E3 ubiquitin ligase RBCK1 confers ferroptosis resistance in pancreatic cancer by facilitating MFN2 degradation. In Free radical biology & medicine, 221, 136-154. doi:10.1016/j.freeradbiomed.2024.05.031. https://pubmed.ncbi.nlm.nih.gov/38763208/

5. Yu, Sifan, Dai, Jie, Ma, Meng, Sheng, Xinan, Guo, Jun. 2019. RBCK1 promotes p53 degradation via ubiquitination in renal cell carcinoma. In Cell death & disease, 10, 254. doi:10.1038/s41419-019-1488-2. https://pubmed.ncbi.nlm.nih.gov/30874541/

6. Liu, Min-Li, Zang, Feng, Zhang, Sheng-Jun. 2019. RBCK1 contributes to chemoresistance and stemness in colorectal cancer (CRC). In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 118, 109250. doi:10.1016/j.biopha.2019.109250. https://pubmed.ncbi.nlm.nih.gov/31545242/