HBP1(高迁移率族蛋白框转录因子1)是一种重要的转录因子,属于高迁移率族蛋白(HMG)家族,具有HMG-box结构域,能够结合DNA并调节基因表达。HBP1在细胞周期调控、代谢、肿瘤抑制等方面发挥着重要作用。HBP1的表达和功能受到多种因素的调控,包括表观遗传修饰、信号通路和微RNA等。
在代谢方面,HBP1通过转录激活胰岛素样生长因子结合蛋白1(IGFBP1)基因,抑制胰岛素样生长因子1(IGF-1)的浓度,从而抑制PI3K/AKT信号通路,动态调节血糖和胰岛素浓度,参与2型糖尿病(T2DM)的发生发展[1]。此外,HBP1还通过转录抑制α-胎蛋白(AFP)基因,抑制AFP对PTEN、MMP9和caspase-3的影响,从而抑制肝癌细胞的增殖和迁移,诱导其凋亡[7]。
在肿瘤抑制方面,HBP1通过多种机制发挥抑癌作用。HBP1通过转录激活组织金属蛋白酶抑制因子3(TIMP3)基因,增加PTEN蛋白水平,抑制MMP2/9的表达,从而抑制乳腺癌的发生发展[4]。HBP1通过抑制UHRF1基因的表达,降低UHRF1蛋白水平,进而通过表观遗传机制上调CDO1基因的表达,增加肿瘤细胞对铁死亡的敏感性,抑制肿瘤的恶性增殖[5]。HBP1还可以通过转录抑制p47phox基因的表达,减少细胞内活性氧(ROS)的产生,从而抑制细胞周期的进程[2]。HBP1通过直接结合AFP基因启动子,抑制AFP基因的表达,从而抑制肝癌细胞的恶性增殖[7]。
HBP1的功能还受到表观遗传修饰的调控。PRMT1介导的HBP1甲基化可以降低HBP1蛋白的稳定性,促进其泛素化和蛋白酶体介导的降解,从而减弱HBP1对肿瘤生长的抑制作用[3]。HBP1的乙酰化可以增强其转录活性,抑制肿瘤细胞的生长[8]。
HBP1的表达和功能受到多种信号通路的调控。PI3K/AKT信号通路可以抑制HBP1的转录和翻译,从而抑制其功能[6]。WNT/β-catenin信号通路中的LEF1、TCF4和MYC等转录因子可以与HBP1结合,抑制其转录活性[6]。此外,多种微RNA,如miR-155、miR-17-92和miR-29a等,可以下调HBP1的表达[6]。
综上所述,HBP1是一种重要的转录因子,在代谢、肿瘤抑制和细胞周期调控等方面发挥着重要作用。HBP1的功能受到多种因素的调控,包括表观遗传修饰、信号通路和微RNA等。深入研究HBP1的调控机制和功能,有助于揭示其在多种疾病发生发展中的作用,为疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Cheng, Yuning, Yang, Ruixiang, Zhou, Yue, Jiang, Wei, Zhang, Xiaowei. 2022. HBP1 inhibits the development of type 2 diabetes mellitus through transcriptional activation of the IGFBP1 gene. In Aging, 14, 8763-8782. doi:10.18632/aging.204364. https://pubmed.ncbi.nlm.nih.gov/36326689/
2. Berasi, Stephen P, Xiu, Mei, Yee, Amy S, Paulson, K Eric. . HBP1 repression of the p47phox gene: cell cycle regulation via the NADPH oxidase. In Molecular and cellular biology, 24, 3011-24. doi:. https://pubmed.ncbi.nlm.nih.gov/15024088/
3. Wang, Jiyin, Yang, Ruixiang, Cheng, Yuning, Jiang, Wei, Zhang, Xiaowei. 2022. Methylation of HBP1 by PRMT1 promotes tumor progression by regulating actin cytoskeleton remodeling. In Oncogenesis, 11, 45. doi:10.1038/s41389-022-00421-7. https://pubmed.ncbi.nlm.nih.gov/35941115/
4. Zhou, Yue, Zhang, Tongjia, Wang, Shujie, Jiang, Wei, Zhang, Xiaowei. 2023. Targeting of HBP1/TIMP3 axis as a novel strategy against breast cancer. In Pharmacological research, 194, 106846. doi:10.1016/j.phrs.2023.106846. https://pubmed.ncbi.nlm.nih.gov/37414199/
5. Yang, Ruixiang, Zhou, Yue, Zhang, Tongjia, Yang, Zhe, Zhang, Xiaowei. 2023. The transcription factor HBP1 promotes ferroptosis in tumor cells by regulating the UHRF1-CDO1 axis. In PLoS biology, 21, e3001862. doi:10.1371/journal.pbio.3001862. https://pubmed.ncbi.nlm.nih.gov/37406020/
6. Bollaert, Emeline, de Rocca Serra, Audrey, Demoulin, Jean-Baptiste. 2019. The HMG box transcription factor HBP1: a cell cycle inhibitor at the crossroads of cancer signaling pathways. In Cellular and molecular life sciences : CMLS, 76, 1529-1539. doi:10.1007/s00018-019-03012-9. https://pubmed.ncbi.nlm.nih.gov/30683982/
7. Cao, Zhengyi, Cheng, Yuning, Wang, Jiyin, Li, Hui, Zhang, Xiaowei. 2021. HBP1-mediated transcriptional repression of AFP inhibits hepatoma progression. In Journal of experimental & clinical cancer research : CR, 40, 118. doi:10.1186/s13046-021-01881-2. https://pubmed.ncbi.nlm.nih.gov/33794968/
8. Raine, E V A, Wreglesworth, N, Dodd, A W, Reynard, L N, Loughlin, J. 2012. Gene expression analysis reveals HBP1 as a key target for the osteoarthritis susceptibility locus that maps to chromosome 7q22. In Annals of the rheumatic diseases, 71, 2020-7. doi:10.1136/annrheumdis-2012-201304. https://pubmed.ncbi.nlm.nih.gov/22586168/