通过SUMOylation调节EMT抑制剂GRHL2的活性
Sonja Santjer1, Yang Xu1, Sabine Riethdorf1
1Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
The Journal of biological chemistry
|September 1, 2025
概括
发育转录因子粒状2 (GRHL2) 通过SUMOylation和酸化进行调节,影响其在癌症中的活性. 错误折叠和核激素形成也抑制GRHL2,突出显示了致癌的复杂控制机制.
科学领域:
- 分子生物学
- 癌症生物学
- 生物化学
背景情况:
- 转录因子粒状2 (GRHL2) 在癌症中具有双重作用,同时作为瘤抑制剂和促进剂.
- 在癌症中控制GRHL2表达和活性的机制在很大程度上是未知的.
研究的目的:
- 阐明控制癌细胞GRHL2活动的调节机制.
- 确定影响GRHL2功能的翻译后修饰和结构性质.
主要方法:
- 酵母两种混合选以识别GRHL2相互作用体.
- SUMOylation和酸化部位的映射 (氨酸159,氨酸164).
- GRHL2的结构分析,包括错误折叠和攻击性形成的倾向.
- 在乳腺癌组织中对GRHL2进行免疫组织化学分析.
主要成果:
- 确定了SUMOylation机械部件作为GRHL2反应器.
- 发现了一个关键的SUMOylation位点 (lysine159),它增强了GRHL2转录活性.
- 发现p38α/β MAPKs酸化 (氨酸164) 和PIAS E3联酶相互作用刺激GRHL2SUMOylation.
- 描述GRHL2是一种内在无序的蛋白质,容易发生核错折和侵略性形成,导致转录抑制.
- 证明了GRHL2亚核定位在乳腺癌发生中的重要性.
结论:
- 通过SUMOylation和酸化,GRHL2活动受到复杂的调节,特定的部位调节其功能.
- 由于GRHL2本质上是无序的,因此有助于通过错误折叠和攻击性形成来调节它.
- GRHL2的亚核分离在乳腺癌的发展中起着至关重要的作用.
相关概念视频
02:04Co-activators and Co-repressors
8.0K
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
8.0K
01:23Regulation of Expression at Multiple Steps
1.2K
The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
1.2K
01:52Eukaryotic Transcription Inhibitors
10.4K
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
10.4K
01:45Regulation of Nuclear Protein Sorting
2.9K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
2.9K
02:36RNA Polymerase II Accessory Proteins
10.2K
Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
10.2K
01:31Regulation of the Unfolded Protein Response
2.8K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.8K