该PRC2.1子综合体通过调节CCND1和CCND2来反对G1的进展
Adam D Longhurst1,2, Kyle Wang3,4, Harsha Garadi Suresh3
1University of California, San Francisco, San Francisco, United States.
eLife
|February 4, 2025
概括
聚抑制剂复合体2 (PRC2.1) 蛋白质MTF2对于细胞循环的进展至关重要. MTF2的损失通过上调CCND1和CCND2对CDK4/6抑制剂产生抗性,从而影响癌细胞的增殖.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 细胞周期的进展,特别是G1阶段,受到严格的调节.
- 识别细胞循环控制的新型调节剂对于理解细胞分裂和开发向疗法的必要.
研究的目的:
- 通过化学遗传方法发现调节细胞循环进展的新型细胞网络.
- 调查聚合物抑制复合体2 (PRC2) 组件在细胞循环调节和对G1/S过渡抑制剂的反应中的作用.
主要方法:
- 化学遗传查,以确定影响对G1/S抑制剂敏感性的基因集群.
- 对包括MTF2和JARID2.2在内的Polycomb Repressor Complex 2 (PRC2) 组件的突变分析.
- 测试评估H3K27me3沉积和CCND1和CCND2.2的基因表达.
主要成果:
- 在PRC2组件的突变中,通过CDK4/6抑制剂palbociclib. 挽救了增殖抑制.
- 失去PRC2.1组件MTF2,但没有PRC2.2组件JARID2,导致对palbociclib的耐药性.
- MTF2对于CpG岛屿的H3K27me3沉积至关重要,包括CCND1和CCND2的促进者,其损失对这些旋风产生了上调.
结论:
- PRC2.1,特别是MTF2,在各种细胞系中对抗G1阶段进展.
- 在调节CCND1/CCND2表达方面,MTF2的作用对于对CDK4/6抑制的敏感性至关重要.
- 这些发现凸显了PRC2.1作为由CDK4/6通路失调驱动的癌症的潜在治疗标.
相关概念视频
01:23Negative Regulator Molecules
35.1K
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
35.1K
02:34Inhibition of Cdk Activity
4.6K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.6K
02:39Positive Regulator Molecules
5.3K
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
5.3K
00:50Anaphase Promoting Complex
2.8K
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
2.8K
01:28The Cell Cycle Control System
2.6K
The cell cycle regulation directs how a cell proceeds from one phase to the next and begins mitosis. The cell cycle control system includes intracellular regulatory molecules and external triggers. They provide "stop" or "advance" signals and operate at specific cell cycle stages termed checkpoints to ensure that a particular process is completed before the cell advances to the next phase.
Cyclins and cyclin-dependent kinases (Cdks) are the primary cell cycle regulators and...
Cyclins and cyclin-dependent kinases (Cdks) are the primary cell cycle regulators and...
2.6K
02:17Separation of Sister Chromatids
3.6K
At the transition from prophase to metaphase, there is a reduction in cohesion along the chromosomal arms, resulting in the resolution of sister chromatids. However, residual cohesin connections remain to hold the sister chromatids together until the transition from metaphase to anaphase. The residual connection prevents any premature separation of sister chromatids, blocking the risks of aneuploidy within the daughter cells.
At the onset of anaphase, separase, a proteolytic enzyme, is...
At the onset of anaphase, separase, a proteolytic enzyme, is...
3.6K