CUL2, a component of the Cullin-RING E3 ubiquitin ligase complex, plays a crucial role in proteolysis, maintaining the balance between normal growth and uncontrolled proliferation [2]. It is involved in multiple biological pathways, such as the regulation of hypoxia-inducible factor (HIF)-mediated transcription and vasculogenesis [4]. Genetic models, like Drosophila, are valuable for studying CUL2 due to its conserved functions across species.

In Drosophila, loss-of-function of Cul2 led to a marked reduction in antimicrobial peptide induction following bacterial infection, associated with increased fly mortality and bacterial load, revealing its importance in the IMD signaling-mediated antimicrobial immune defense [6]. In human studies, in NSCLC, down-regulation of Circ-CUL2 was associated with cisplatin resistance, and restoring Circ-CUL2 enhanced the sensitivity of A549/DDP cells to DDP [1]. In prostate tumors, CUL2 was highly expressed and associated with biochemical failure after salvage therapy [2]. In pancreatic ductal adenocarcinoma, circSTX6 interacted with CUL2 to promote tumor proliferation and metastasis [3]. In HNSCC, up-regulation of CUL2 was linked to clinicopathological features, overall survival, and it could promote cellular proliferation and migration [5].

In conclusion, CUL2 is essential for various biological functions including proteolysis, immune defense, and regulation of HIF-mediated transcription. Studies on CUL2 using model-based research, especially in Drosophila and human cancer tissues, have revealed its significant role in diseases such as cancer and in the context of chemotherapy resistance. Understanding CUL2 can potentially offer new strategies for treating related diseases.

References:

1. Chen, HengQi, Li, Fang, Xue, Qi. . Circ-CUL2/microRNA-888-5p/RB1CC1 axis participates in cisplatin resistance in NSCLC via repressing cell advancement. In Bioengineered, 13, 2828-2840. doi:10.1080/21655979.2021.2024395. https://pubmed.ncbi.nlm.nih.gov/35068326/

2. Hirth, Carlos Gustavo, Vasconcelos, Gislane Rocha, da Cunha, Maria do Perpétuo Socorro Saldanha, Leite, Carlos Heli Bezerra, Dornelas, Conceição Aparecida. 2021. Immunoexpression of HSPA9 and CUL2 in prostatic tissue and adenocarcinoma. In Annals of diagnostic pathology, 56, 151843. doi:10.1016/j.anndiagpath.2021.151843. https://pubmed.ncbi.nlm.nih.gov/34717191/

3. Meng, Lingdong, Zhang, Yihan, Wu, Pengfei, Tu, Min, Jiang, Kuirong. 2022. CircSTX6 promotes pancreatic ductal adenocarcinoma progression by sponging miR-449b-5p and interacting with CUL2. In Molecular cancer, 21, 121. doi:10.1186/s12943-022-01599-5. https://pubmed.ncbi.nlm.nih.gov/35650603/

4. Maeda, Yutaka, Suzuki, Takuji, Pan, Xiufang, Bartman, Thomas, Whitsett, Jeffrey A. 2008. CUL2 is required for the activity of hypoxia-inducible factor and vasculogenesis. In The Journal of biological chemistry, 283, 16084-92. doi:10.1074/jbc.M710223200. https://pubmed.ncbi.nlm.nih.gov/18372249/

5. Xu, Bingqing, Wang, Ruohuang, Zhang, Jisheng, Du, Xiaoyun, Jiang, Yan. . Bioinformatics analysis of CUL2/4A/9 and its function in head and neck squamous cell carcinoma. In Endokrynologia Polska, 74, 315-330. doi:10.5603/EP.a2023.0029. https://pubmed.ncbi.nlm.nih.gov/37695034/

6. Duan, Renjie, Hu, Baoyi, Ding, Erwen, Cai, Qingshuang, Ji, Shanming. 2025. Cul2 Is Essential for the Drosophila IMD Signaling-Mediated Antimicrobial Immune Defense. In International journal of molecular sciences, 26, . doi:10.3390/ijms26062627. https://pubmed.ncbi.nlm.nih.gov/40141268/