损害的CDK12活性导致对O-GlcNAc转移酶的高活性产生依赖
Satu Pallasaho1, Aishwarya Gondane1, Julia Kutz2
1Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.
Glycobiology
|October 3, 2024
概括
向O-GlcNAc转移酶 (OGT) 和循环素依赖激酶12 (CDK12) 显示在前列腺癌中具有毒性. 抑制CDK12揭示SRPK1作为一个合成致命的目标,提供新的治疗策略.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- O-GlcNAc转移酶 (OGT) 对于细胞功能至关重要,并与转录调节剂如循环林依赖激酶12 (CDK12) 合作.
- CDK12是一种关键的转录延长激酶,其活性与包括前列腺癌在内的各种癌症有关.
研究的目的:
- 研究在前列腺癌中联合准OGT和CDK12的治疗潜力.
- 确定与前列腺癌中CDK12失活相关的新型治疗漏洞.
主要方法:
- 利用基于抑制剂和淘汰的策略来评估OGT和CDK12共同向的影响.
- 采用糖蛋白组学来分析O-GlcNAcylation在对CDK12抑制的反应中的变化.
- 综合糖蛋白组学,基因基本性和前列腺癌患者的临床数据.
主要成果:
- 同时准OGT和CDK12表明对前列腺癌细胞有毒性.
- 短期的CDK12抑制导致了结合体机械的超O-GlcNAcylation.
- 鉴定了氨酸-氨酸蛋白激酶1 (SRPK1) 作为合成致命的合作伙伴与CDK12失活.
结论:
- 降低CDK12活性的前列腺癌细胞对OGT和SRPK1抑制剂高度敏感.
- 在侵袭性前列腺癌中普遍存在的 CDK12 突变的非活化表明,结合酶体向疗法的潜在益处.
更多相关视频
09:13Author Spotlight: Identifying Compensatory Pathways in Malaria Parasites Containing Hypomorphic Allele of Essential Protein Kinases
Published on: November 22, 2024
1.7K
10:49A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers
Published on: September 26, 2019
5.8K
相关概念视频
02:34Inhibition of Cdk Activity
5.3K
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...
5.3K
02:39Positive Regulator Molecules
6.1K
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.
6.1K
01:45Positive Regulator Molecules
117.6K
To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
117.6K
02:15M-Cdk Drives Transition Into Mitosis
5.9K
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.9K
00:50Anaphase Promoting Complex
3.1K
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...
3.1K
01:25cAMP-dependent Protein Kinase Pathways
7.3K
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
7.3K