核至细胞质运输是MYC驱动的肝细胞癌中可药物依赖的药物依赖
Anja Deutzmann1, Delaney K Sullivan1, Renumathy Dhanasekaran1,2
1Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, 94305, USA.
Nature communications
|February 1, 2024
概括
我们在高MYC肝癌细胞中确定了对生存至关重要的基因,揭示了核细胞质运输作为关键漏洞. 向输出素-1 (XPO1) 在治疗MYC驱动的肝细胞癌 (HCC) 中表现有前途.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 在人类癌症中,MYC瘤基因经常失调,包括肝细胞癌 (HCC).
- 目前,MYC被认为是无法治疗的癌症标.
- 识别MYC驱动癌症的脆弱性对于治疗开发至关重要.
研究的目的:
- 为了确定基因对于MYC高细胞在HCC的生存至关重要.
- 为了发现与MYC的新型合成致命相互作用.
- 为了研究针对已识别的MYC-合成致命相互作用的治疗潜力.
主要方法:
- 在MYC条件的HCC模型中进行了全基因组的CRISPR/Cas9选.
- 分析了小鼠HCC和人类HCC患者队列中的基因表达和生存数据.
- 在临床前HCC模型中评估出口素-1 (XPO1) 抑制的体内疗效.
主要成果:
- 发现了新的MYC合成致命 (MYC-SL) 相互作用,核细胞质运输成为一个关键的漏洞.
- 发现大多数MYC-SL核细胞质运输基因在MYC高的小鼠HCC中被上调,并与患者生存率差相关.
- 在HCC模型中通过准XPO1 in vivo显著的瘤回归和生长抑制.
- 观察到,XPO1在HCC的预后意义仅限于MYC活性高的患者.
结论:
- 核细胞质运输是MYC驱动的HCC的一个关键依赖和潜在的治疗目标.
- 抑制XPO1显示了肝细胞癌与高MYC表达的治疗前景.
- MYC可能广泛调节并需要改变瘤发生的核细胞质运输基因表达.
相关概念视频
Nuclear Protein Sorting
4.6K
Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
4.6K
Nuclear Export
3.6K
The nucleus restricts several proteins within and allows others to pass. The restricted proteins possess a nuclear retention sequence or NRS, anchoring them to the nuclear lamins and preventing their transport to the cytosol. The non-restricted proteins, after their synthesis, are transported to their site of action, such as the cytosol or other organelles, with the help of nuclear export signals or NES.
NES are of three types- the canonical 10-residue long leucine-rich signal and other...
NES are of three types- the canonical 10-residue long leucine-rich signal and other...
3.6K
Directionality of Nuclear Transport
3.2K
Ras-related nuclear protein or Ran is a small G protein that cycles between its GTP and GDP bound states. Ran specific regulators, a Ran GTPase Activating Protein or RanGAP present in the cytosol and a Ran guanine nucleotide exchange factor or RanGEF present inside the nucleus regulate GTP/GDP exchange. A high concentration of GTP inside the cells, in addition to this asymmetric distribution of Ran-specific regulators, leads to a higher RanGTP concentration inside the nucleus. This...
3.2K
Regulation of Nuclear Protein Sorting
2.4K
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...
2.4K
Nuclear Export of mRNA
7.7K
Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
7.7K
Nuclear Localization Signals and Import
5.7K
Proteins targeted to the nucleus carry short stretches of amino acid sequences called the nuclear localization signal or NLS. Classical nuclear localization signals are of two types: monopartite and bipartite NLS. Monopartite classical NLS (cNLS) consists of a single cluster of 4-8 amino acids. Bipartite cNLS consists of two clusters of 2-3 amino acids and a 9-12 residue long proline-rich linker bridging the two clusters. Signal clusters are rich in positively charged amino acids such as...
5.7K


