| Autor: |
Zhiqiang Chen, Xinyi Zhou, Xiaojun Zhou, Yi Tang, Mingzhu Lu, Jianhong Zhao, Chenhui Tian, Mingzhi Wu, Yanliang Liu, Edward V. Prochownik, Fubing Wang, Youjun Li |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Advanced Science, Vol 10, Iss 12, Pp n/a-n/a (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2198-3844 |
| DOI: |
10.1002/advs.202204909 |
| Popis: |
Abstract β‐catenin signaling is abnormally activated in cancer. Here, this work screens the mevalonate metabolic pathway enzyme PMVK to stabilize β‐catenin signaling using a human genome‐wide library. On the one hand, PMVK‐produced MVA‐5PP competitively binds to CKIα to prevent β‐catenin Ser45 phosphorylation and degradation. On the other hand, PMVK functions as a protein kinase to directly phosphorylate β‐catenin Ser184 to increase its protein nuclear localization. This synergistic effect of PMVK and MVA‐5PP together promotes β‐catenin signaling. In addition, PMVK deletion impairs mouse embryonic development and causes embryonic lethal. PMVK deficiency in liver tissue alleviates DEN/CCl4‐induced hepatocarcinogenesis. Finally, the small molecule inhibitor of PMVK, PMVKi5, is developed and PMVKi5 inhibits carcinogenesis of liver and colorectal tissues. These findings reveal a non‐canonical function of a key metabolic enzyme PMVK and a novel link between the mevalonate pathway and β‐catenin signaling in carcinogenesis providing a new target for clinical cancer therapy. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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