在骨髓瘤中,USP1使ID蛋白二分化,以保存一个介酶干细胞程序
Samuel A Williams1, Heather L Maecker, Dorothy M French
1Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Cell
|September 20, 2011
概括
双化酶USP1稳定了DNA结合 (ID) 蛋白的抑制剂,保持了骨髓瘤中干细胞的特征. 向USP1可能为骨髓瘤分化疗法提供一种新的治疗策略.
科学领域:
- 分子生物学分子生物学
- 癌症生物学 癌症生物学
- 干细胞生物学 干细胞生物学
背景情况:
- 通过抑制分化,DNA结合 (ID) 蛋白的抑制剂对于维持干细胞命运至关重要.
- 虽然ID蛋白通常在差异化组织中降解,但它们通常在瘤中存在.
- 在癌症中调节ID蛋白稳定性的机制仍然不完全理解.
研究的目的:
- 为了研究二维基化酶USP1在调节ID蛋白稳定性中的作用.
- 确定USP1对骨髓瘤干细胞类特征的贡献.
- 探索USP1作为骨髓瘤的潜在治疗点.
主要方法:
- 免疫沉和西部斑点测试以评估USP1-ID蛋白相互作用和无处不在状态.
- 在骨髓瘤和介质干细胞中USP1敲击和过度表达实验.
- 细胞增殖,细胞循环停止和骨质分化标志物的评估.
- 在初级人类骨髓瘤样本中分析USP1和ID蛋白表达.
- 对缺乏USP1的小鼠进行表型分析.
主要成果:
- USP1直接与ID1,ID2和ID3结合并分离,从而稳定这些蛋白质.
- 观察到USP1和ID蛋白的联合过度表达在人类骨髓瘤的一个子集中.
- 在骨髓瘤细胞中USP1的敲击导致ID蛋白的不稳定,细胞循环停止,并诱导骨质分化.
- 介细胞干细胞中异位USP1表达促进了增殖,并抑制了骨质母细胞的分化.
- 在小鼠中USP1缺乏导致骨质疏松症,表明其在骨质稳定中的作用.
结论:
- USP1在稳定ID蛋白中起着至关重要的作用,促进骨髓瘤中类似干细胞的特性.
- USP1与保持骨髓瘤特征的干细胞状态有关.
- USP1代表了一个有前途的治疗点,用于诱导骨髓瘤的分化.
相关概念视频
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
01:13The Proteasome
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
02:18The Proteasome
Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
02:58Regulated Protein Degradation
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
01:19Mesenchymal Stem Cells
Mesenchymal stem cells (MSCs) are adult stem cells that can differentiate into most connective tissue cell types, except for hematopoietic cells, depending upon the source of MSCs. For example, bone-marrow-derived MSCs (BM-MSCs) can differentiate into osteocytes, hepatocytes, and pancreatic and neuronal cells. MSCs can be isolated from various sources such as bone marrow, placenta, adipose tissue, teeth, and Wharton’s jelly, a gelatinous substance in the umbilical cord. The ease of their access...
02:04Covalently Linked Protein Regulators
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
These groups modify specific amino acids in a protein.