Dtx1, also known as Deltex E3 ubiquitin ligase 1, is a key regulator involved in multiple biological processes. It is closely associated with the Notch signaling pathway, where it functions as a negative regulator [2,5,6]. Dtx1 also participates in cell growth, differentiation, apoptosis, and intracellular signal transduction [3].

In the context of lymphatic development, knockdown of Dtx1 in cultured lymphatic endothelial cells inhibited laminar flow-induced calcium influx and abrogated the flow-mediated regulation of genes involved in lymphatic sprouting, suggesting its importance in the Piezo1-ORAI1-regulated mechanotransduction pathway for lymphatic expansion [1]. In hepatocytes, overexpression of Dtx1 inhibited D-GalN/TNF-α-induced pyroptosis and inflammation by regulating NLRP3 ubiquitination [3]. In pancreatic β-cells, miR-210-3p impairs cell function by targeting Dtx1, and down-expression of Dtx1 can boost pancreatic β-cell function [4]. Regarding cancer, the genetic variant DTX1 rs1732786A > G was associated with better prognosis in early-stage non-small cell lung cancer (NSCLC) but worse prognosis in small cell lung cancer (SCLC) [5,6]. Also, eccDNA containing Dtx1 promotes cell growth in hydroquinone-induced malignantly transformed cells by regulating Dtx1 transcription [7].

In summary, Dtx1 plays diverse and crucial roles in biological processes such as lymphatic development, cell pyroptosis and inflammation, pancreatic β-cell function, and cancer prognosis. Gene knockout or knockdown models in various cell types and animal models have been instrumental in revealing these functions, contributing to our understanding of related biological processes and disease mechanisms in areas like lymphatic malformations, acute liver injury, gestational diabetes mellitus, and lung cancer [1,4-7,10].

References:

1. Choi, Dongwon, Park, Eunkyung, Yu, Roy P, Wong, Alex K, Hong, Young-Kwon. 2022. Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion. In Circulation research, 131, e2-e21. doi:10.1161/CIRCRESAHA.121.320565. https://pubmed.ncbi.nlm.nih.gov/35701867/

2. Zheng, Li, Conner, Sean D. 2018. PI5P4Kγ functions in DTX1-mediated Notch signaling. In Proceedings of the National Academy of Sciences of the United States of America, 115, E1983-E1990. doi:10.1073/pnas.1712142115. https://pubmed.ncbi.nlm.nih.gov/29440432/

3. Liu, Mingshui, Gu, Jing, Chen, Li, Huang, Xiaoping, Gan, Jianhe. 2024. Overexpression of DTX1 inhibits D-GalN/TNF-α-induced pyroptosis and inflammation in hepatocytes by regulating NLRP3 ubiquitination. In Toxicology research, 13, tfae145. doi:10.1093/toxres/tfae145. https://pubmed.ncbi.nlm.nih.gov/39319341/

4. Cao, Xiaohui, Lu, Bin, Gu, Ying, Guo, Danfeng, Xia, Fei. . miR-210-3p Impairs Pancreatic β-Cell Function by Targeting Dtx1 in Gestational Diabetes Mellitus. In Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer, 41, 11-23. doi:10.1615/JEnvironPatholToxicolOncol.2022041670. https://pubmed.ncbi.nlm.nih.gov/36374959/

5. Yoo, Seung Soo, Lee, Jang Hyuck, Hong, Mi Jeong, Kim, Chang Ho, Park, Jae Yong. 2020. Effect of genetic variation in Notch regulator DTX1 on SCLC prognosis compared with the effect on NSCLC prongosis. In Thoracic cancer, 11, 2698-2703. doi:10.1111/1759-7714.13566. https://pubmed.ncbi.nlm.nih.gov/32700476/

6. Lee, Jang Hyuck, Shin, Kyung Min, Lee, Shin Yup, Kim, Dong Kwan, Park, Jae Yong. 2019. Genetic Variant of Notch Regulator DTX1 Predicts Survival After Lung Cancer Surgery. In Annals of surgical oncology, 26, 3756-3764. doi:10.1245/s10434-019-07614-2. https://pubmed.ncbi.nlm.nih.gov/31313037/

7. Ling, Xiaoxuan, Jiao, Qunfang, Lin, Daifan, Ruan, Yongdui, Liu, Linhua. 2024. Extrachromosomal circular DNA containing DTX1 promotes cell growth in hydroquinone-induced malignantly transformed cells by regulating the transcription of DTX1. In BMC cancer, 24, 1448. doi:10.1186/s12885-024-13177-7. https://pubmed.ncbi.nlm.nih.gov/39587541/