Laboratory of Analysis of Chromosomal Proteins, Department of Cell Biology and Radiobiology, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic.
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
FASEB J. 2019 Dec 1;33(12):14307-14324. doi: 10.1096/fj.201901465RRR. Epub 2019 Oct 26.
High-mobility group box (HMGB)1 and HMGB2 proteins are the subject of intensive research because of their involvement in DNA replication, repair, transcription, differentiation, proliferation, cell signaling, inflammation, and tumor migration. Using inducible, stably transfected human embryonic stem cells (hESCs) capable of the short hairpin RNA-mediated knockdown (KD) of and , we provide evidence that deregulation of or expression in hESCs and their differentiated derivatives (neuroectodermal cells) results in distinct modulation of telomere homeostasis. Whereas HMGB1 enhances telomerase activity, HMGB2 acts as a negative regulator of telomerase activity in the cell. Stimulation of telomerase activity in the HMGB2-deficient cells may be related to activation of the PI3K/protein kinase B/ glycogen synthase kinase-3β/β-catenin signaling pathways by HMGB1, augmented TERT/telomerase RNA subunit transcription, and possibly also because of changes in telomeric repeat-containing RNA (TERRA) and TERRA-polyA transcription. The impact of KD on telomerase transcriptional regulation observed in neuroectodermal cells is partially masked in hESCs by their pluripotent state. Our findings on differential roles of HMGB1 and HMGB2 proteins in regulation of telomerase activity may suggest another possible outcome of HMGB1 targeting in cells, which is currently a promising approach aiming at increasing the anticancer activity of cytotoxic agents.-Kučírek, M., Bagherpoor, A. J., Jaroš, J., Hampl, A., Štros, M. HMGB2 is a negative regulator of telomerase activity in human embryonic stem and progenitor cells.
高迁移率族蛋白 B1（HMGB1）和 HMGB2 蛋白是研究的热点，因为它们参与 DNA 复制、修复、转录、分化、增殖、细胞信号转导、炎症和肿瘤迁移。我们使用可诱导的、稳定转染的人胚胎干细胞（hESCs），这些细胞能够通过短发夹 RNA 介导的 knockdown（KD）下调 和 ，提供证据表明 hESCs 及其分化衍生物（神经外胚层细胞）中 或 的表达失调会导致端粒稳态的明显调节。HMGB1 增强端粒酶活性，而 HMGB2 作为细胞中端粒酶活性的负调节剂。HMGB2 缺陷细胞中端粒酶活性的刺激可能与 HMGB1 激活 PI3K/蛋白激酶 B/糖原合成酶激酶-3β/β-catenin 信号通路、增强 TERT/端粒酶 RNA 亚基转录有关，并且可能还与端粒重复序列含有 RNA（TERRA）和 TERRA-polyA 转录的变化有关。在神经外胚层细胞中观察到的 KD 对端粒酶转录调控的影响，在 hESCs 中由于其多能状态而部分被掩盖。我们发现 HMGB1 和 HMGB2 蛋白在调节端粒酶活性方面的不同作用，这可能表明 HMGB1 靶向细胞的另一种可能结果，目前这是一种有前途的方法，旨在提高细胞毒性药物的抗癌活性。-Kučírek, M., Bagherpoor, A. J., Jaroš, J., Hampl, A., Štros, M. HMGB2 是人类胚胎干细胞和祖细胞中端粒酶活性的负调节剂。
