基因THEM4,全称为硫酯酶超家族成员4(Thioesterase superfamily member 4),属于硫酯酶超家族,是一种与多种生物学过程相关的酶。THEM4在脂质代谢中起着重要作用,通过催化酰基辅酶A(acyl-CoA)的分解,维持细胞内非酯化脂肪酸和激活脂肪酸的平衡,以及辅酶A的水平[5]。此外,THEM4还参与炎症反应和细胞增殖等过程。
THEM4与Akt信号通路的关系是当前研究的热点。Akt是一种重要的蛋白激酶,通过磷酸化下游靶基因来调控细胞的生长、增殖和代谢等过程。THEM4作为Akt激酶的结合蛋白,可以与Akt结合并调节其磷酸化水平[1]。在某些研究中,THEM4被认为是Akt的内源性抑制剂,在肺癌、胰腺癌和肝癌等疾病中抑制Akt的磷酸化,从而发挥抑癌作用[1]。然而,在其他研究中,THEM4则被证明可以促进肿瘤细胞的增殖,如乳腺癌和鼻咽癌,通过与Akt结合正向调节Akt活性[1]。因此,THEM4在Akt通路中的作用是复杂的,具有双刃剑效应。
除了在Akt通路中的作用,THEM4还与其他信号通路相关。例如,CARD9是一种与胆管癌相关的基因,可以通过与THEM4相互作用,促进Akt和mTOR的磷酸化,从而加速胆管癌的进展[2]。此外,THEM4还与疟疾感染相关,在非洲儿童中,THEM4被鉴定为与恶性疟原虫感染相关的关键基因[3]。在自身免疫性甲状腺炎患者中,THEM4基因的DNA甲基化水平发生改变,可能与碘的摄入水平相关[4]。
在遗传学方面,THEM4基因的多态性与2型糖尿病的易感性相关。研究发现,THEM4基因中存在一个顺式调控单核苷酸多态性(cis-eQTL),可能通过调节THEM4的表达影响葡萄糖稳态,从而影响2型糖尿病的易感性[6]。此外,维生素D可以通过上调THEM4的表达来抑制COX-2的表达和炎症反应[7]。
综上所述,基因THEM4在脂质代谢、炎症反应、细胞增殖和疾病发生中发挥重要作用。THEM4与Akt信号通路的关系复杂,具有双刃剑效应。THEM4还与其他信号通路相关,如CARD9信号通路和维生素D信号通路。此外,THEM4基因的多态性与2型糖尿病的易感性相关。THEM4的研究有助于深入理解其在生物学过程中的作用和疾病发生机制,为疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Xie, Wen, Liu, Weidong, Wang, Lei, Liu, Jie, Ren, Caiping. . Roles of THEM4 in the Akt pathway: a double-edged sword. In Journal of Zhejiang University. Science. B, 25, 541-556. doi:10.1631/jzus.B2300457. https://pubmed.ncbi.nlm.nih.gov/39011675/
2. Zhang, Tao, Zhu, Li-Xin, Sun, Qi-Kai, Chen, Li-Jian, Qian, Ye-Ben. 2024. CARD9 promotes cholangiocarcinoma by regulating the IL-17A/Hedgehog and the THEM4/AKT/mTOR signaling pathways. In International immunopharmacology, 143, 113399. doi:10.1016/j.intimp.2024.113399. https://pubmed.ncbi.nlm.nih.gov/39418733/
3. Nambou, Komi, Nie, Xiaoling, Tong, Yin, Anakpa, Manawa. 2021. Weighted gene co-expression network analysis and drug-gene interaction bioinformatics uncover key genes associated with various presentations of malaria infection in African children and major drug candidates. In Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 89, 104723. doi:10.1016/j.meegid.2021.104723. https://pubmed.ncbi.nlm.nih.gov/33444859/
4. Ren, Bingxuan, Wan, Siyuan, Wu, Huaiyong, Zhou, Zheng, Shen, Hongmei. 2022. Effect of different iodine levels on the DNA methylation of PRKAA2, ITGA6, THEM4 and PRL genes in PI3K-AKT signaling pathway and population-based validation from autoimmune thyroiditis patients. In European journal of nutrition, 61, 3571-3583. doi:10.1007/s00394-022-02907-x. https://pubmed.ncbi.nlm.nih.gov/35622138/
5. Brocker, Chad, Carpenter, Christopher, Nebert, Daniel W, Vasiliou, Vasilis. . Evolutionary divergence and functions of the human acyl-CoA thioesterase gene ( ACOT ) family. In Human genomics, 4, 411-20. doi:. https://pubmed.ncbi.nlm.nih.gov/20846931/
6. Mondal, Ashis K, Sharma, Neeraj K, Elbein, Steven C, Das, Swapan K. 2013. Allelic expression imbalance screening of genes in chromosome 1q21-24 region to identify functional variants for Type 2 diabetes susceptibility. In Physiological genomics, 45, 509-20. doi:10.1152/physiolgenomics.00048.2013. https://pubmed.ncbi.nlm.nih.gov/23673729/
7. Wang, Qingsong, He, Yuhu, Shen, Yujun, Wang, Junwen, Yu, Ying. 2014. Vitamin D inhibits COX-2 expression and inflammatory response by targeting thioesterase superfamily member 4. In The Journal of biological chemistry, 289, 11681-11694. doi:10.1074/jbc.M113.517581. https://pubmed.ncbi.nlm.nih.gov/24619416/