Uprt-KO Mouse

Uprt, or uracil phosphoribosyltransferase, is an enzyme in the pyrimidine salvage pathway. It catalyzes the conversion of uracil to uridine monophosphate (UMP). The enzyme is highly conserved across organisms from prokaryotes to humans [1].

In Drosophila, the UPRT homologue krishah (kri) is essential for larval growth, pre-pupal/pupal viability, and long-term adult lifespan, suggesting that UPRT in higher eukaryotes is likely enzymatically active in vivo and is not non-essential as previously thought [1]. Engineered vaccinia virus armed with CD/UPRT can convert 5-fluorocytosine (5-FC) into chemotherapeutic agents, showing anti-tumor effects against pancreatic ductal adenocarcinoma in mice [2]. miR-3200 affects the translational ability of the UPRT gene, accelerating the growth of liver cancer cells [3]. In a mouse model expressing Rosa26-floxed-stop Uprt, 4-thiouracil (4-TU) was used to tag nascent RNA, revealing cell-and stimulus-specific responses to acute kidney injury [4]. In glioma gene therapy, UPRT in the CD::UPRT/5-FC system can catalyze 5-FU to 5-fluorouridine monophosphate, showing a bystander effect [5]. Transgenic zebrafish with hepatocyte-specific UPRT expression helped identify a metabolic transition and the role of Nrf2 in liver regeneration [6]. Oncolytic adenovirus expressing UPRT enhanced the toxicity of 5-fluorouracil (5-FU) in immunocompetent Syrian hamsters, and cyclophosphamide further increased its antitumor efficacy [7]. Arabidopsis thaliana UPRT (AtUPRT) sensitized HeLa cells to 5-FU, causing apoptosis and cell cycle arrest [8].

In summary, Uprt is crucial in the pyrimidine salvage pathway, and its functions extend to various biological processes such as larval development, tumorigenesis, and tissue injury responses. Model-based research, including those in Drosophila, mice, zebrafish, and cell lines, has revealed its significance in different disease conditions like cancer, indicating its potential as a therapeutic target or part of gene-therapy strategies.

References:

1. Ghosh, Arpan C, Shimell, MaryJane, Leof, Emma R, Haley, Macy J, O'Connor, Michael B. 2015. UPRT, a suicide-gene therapy candidate in higher eukaryotes, is required for Drosophila larval growth and normal adult lifespan. In Scientific reports, 5, 13176. doi:10.1038/srep13176. https://pubmed.ncbi.nlm.nih.gov/26271729/

2. Kurosaki, Hajime, Nakatake, Motomu, Sakamoto, Teruhisa, Fujiwara, Yoshiyuki, Nakamura, Takafumi. 2021. Anti-Tumor Effects of MAPK-Dependent Tumor-Selective Oncolytic Vaccinia Virus Armed with CD/UPRT against Pancreatic Ductal Adenocarcinoma in Mice. In Cells, 10, . doi:10.3390/cells10050985. https://pubmed.ncbi.nlm.nih.gov/33922406/

3. Song, Shuting, Xie, Sijie, Liu, Xinlei, Jiang, Xiaoxue, Lu, Dongdong. 2023. miR-3200 accelerates the growth of liver cancer cells by enhancing Rab7A. In Non-coding RNA research, 8, 675-685. doi:10.1016/j.ncrna.2023.10.005. https://pubmed.ncbi.nlm.nih.gov/37860266/

4. Shen, Tian Huai, Stauber, Jacob, Xu, Katherine, Tatonetti, Nicholas P, Barasch, Jonathan. 2022. Snapshots of nascent RNA reveal cell- and stimulus-specific responses to acute kidney injury. In JCI insight, 7, . doi:10.1172/jci.insight.146374. https://pubmed.ncbi.nlm.nih.gov/35230973/

5. Shi, De-zhi, Hu, Wei-xing, Li, Li-xin, Wei, Dong, Gu, Pei-yuan. . Pharmacokinetics and the bystander effect in CD::UPRT/5-FC bi-gene therapy of glioma. In Chinese medical journal, 122, 1267-72. doi:. https://pubmed.ncbi.nlm.nih.gov/19567135/

6. Tan, Vicky W T, Salmi, Talhah M, Karamalakis, Anthony P, Dawson, Mark A, Cox, Andrew G. 2024. SLAM-ITseq identifies that Nrf2 induces liver regeneration through the pentose phosphate pathway. In Developmental cell, 59, 898-910.e6. doi:10.1016/j.devcel.2024.01.024. https://pubmed.ncbi.nlm.nih.gov/38366599/

7. Hasegawa, Naoyuki, Abei, Masato, Yokoyama, Kazunari K, Obata, Yuichi, Hyodo, Ichinosuke. 2013. Cyclophosphamide enhances antitumor efficacy of oncolytic adenovirus expressing uracil phosphoribosyltransferase (UPRT) in immunocompetent Syrian hamsters. In International journal of cancer, 133, 1479-88. doi:10.1002/ijc.28132. https://pubmed.ncbi.nlm.nih.gov/23444104/

8. Narayanan, Sharmila, Sanpui, Pallab, Sahoo, Lingaraj, Ghosh, Siddhartha Sankar. 2016. Unravelling the potential of a new uracil phosphoribosyltransferase (UPRT) from Arabidopsis thaliana in sensitizing HeLa cells towards 5-fluorouracil. In International journal of biological macromolecules, 91, 310-6. doi:10.1016/j.ijbiomac.2016.05.037. https://pubmed.ncbi.nlm.nih.gov/27180296/