Fbxo31,也称为F-box蛋白31,是一种重要的E3泛素连接酶的底物识别亚基。E3泛素连接酶负责将泛素分子添加到目标蛋白上,从而标记它们进行降解。Fbxo31在细胞周期调控、DNA复制、神经元发育和肿瘤抑制中发挥着重要作用。
Fbxo31在多种癌症中发挥肿瘤抑制功能。研究发现,Fbxo31的表达水平与乳腺癌、食管鳞状细胞癌和前列腺癌的预后密切相关。在乳腺癌细胞系中,Fbxo31的表达下调与细胞增殖和转移增加相关。在食管鳞状细胞癌细胞中,Fbxo31的表达下调与对化疗药物Taxol的耐药性相关。在前列腺癌细胞中,Fbxo31的表达下调与肿瘤的发生和发展相关[2,4,5,7]。Fbxo31通过与不同的底物相互作用,调控细胞周期蛋白D1、p53拮抗剂MDM2、DNA复制因子Cdt1和双重特异性磷酸酶DUSP6的降解,从而影响细胞周期进程、DNA复制和信号转导途径[1,3,5,6]。
Fbxo31还在神经元发育中发挥重要作用。研究发现,Fbxo31的突变与脑瘫的发生相关。Fbxo31作为SCF复合物的一部分,参与神经元形态发生和轴突身份的调控。Fbxo31的突变导致神经元迁移和突触形成受损,从而影响神经系统的正常发育[8]。
此外,Fbxo31的表达还受到细胞内信号通路的调控。研究发现,AKT和ATM激酶的磷酸化可以调节Fbxo31的降解。AKT激酶的磷酸化可以促进Fbxo31与APC/C复合物的结合,从而促进其泛素化和降解。而ATM激酶的磷酸化可以阻止Fbxo31与APC/C复合物的结合,从而保护Fbxo31免受降解。这些发现揭示了Fbxo31在正常细胞和DNA损伤应激下的生理调节机制[3]。
综上所述,Fbxo31是一种重要的E3泛素连接酶底物识别亚基,在细胞周期调控、DNA复制、神经元发育和肿瘤抑制中发挥着重要作用。Fbxo31的表达水平和功能异常与多种癌症的发生和发展相关。Fbxo31的研究有助于深入理解细胞周期进程、DNA复制和神经元发育的调控机制,为癌症治疗和神经系统疾病的治疗提供新的思路和策略。
参考文献:
1. Jin, Sheng Chih, Lewis, Sara A, Bakhtiari, Somayeh, MacLennan, Alastair H, Kruer, Michael C. 2020. Mutations disrupting neuritogenesis genes confer risk for cerebral palsy. In Nature genetics, 52, 1046-1056. doi:10.1038/s41588-020-0695-1. https://pubmed.ncbi.nlm.nih.gov/32989326/
2. Kumar, Raman, Neilsen, Paul M, Crawford, Joanne, Cleton-Jansen, Anne-Marie, Callen, David F. . FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex. In Cancer research, 65, 11304-13. doi:. https://pubmed.ncbi.nlm.nih.gov/16357137/
3. Choppara, Srinadh, Malonia, Sunil K, Sankaran, Ganga, Green, Michael R, Santra, Manas Kumar. 2018. Degradation of FBXO31 by APC/C is regulated by AKT- and ATM-mediated phosphorylation. In Proceedings of the National Academy of Sciences of the United States of America, 115, 998-1003. doi:10.1073/pnas.1705954115. https://pubmed.ncbi.nlm.nih.gov/29343641/
4. Lv, Liang, Wang, Shu Chao, Mo, Jin You, Xu, Mei Li, Liu, Jia. 2021. Effects and mechanisms of FBXO31 on Taxol chemoresistance in esophageal squamous cell carcinoma. In Biochemical and biophysical research communications, 586, 129-136. doi:10.1016/j.bbrc.2021.11.082. https://pubmed.ncbi.nlm.nih.gov/34839191/
5. Duan, Shanshan, Moro, Loredana, Qu, Rui, Arbini, Arnaldo A, Pagano, Michele. . Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis. In Cell reports, 37, 109870. doi:10.1016/j.celrep.2021.109870. https://pubmed.ncbi.nlm.nih.gov/34686346/
6. Johansson, Pegah, Jeffery, Jessie, Al-Ejeh, Fares, Kumar, Raman, Khanna, Kum Kum. 2014. SCF-FBXO31 E3 ligase targets DNA replication factor Cdt1 for proteolysis in the G2 phase of cell cycle to prevent re-replication. In The Journal of biological chemistry, 289, 18514-25. doi:10.1074/jbc.M114.559930. https://pubmed.ncbi.nlm.nih.gov/24828503/
7. Kogo, Ryunosuke, Mimori, Koshi, Tanaka, Fumiaki, Komune, Shizuo, Mori, Masaki. 2011. FBXO31 determines poor prognosis in esophageal squamous cell carcinoma. In International journal of oncology, 39, 155-9. doi:10.3892/ijo.2011.1018. https://pubmed.ncbi.nlm.nih.gov/21537837/
8. Mir, Asif, Sritharan, Kumudesh, Mittal, Kirti, Ayub, Muhammad, Vincent, John B. 2014. Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability in a Pakistani family. In Human genetics, 133, 975-84. doi:10.1007/s00439-014-1438-0. https://pubmed.ncbi.nlm.nih.gov/24623383/