期刊
MOLECULAR ONCOLOGY
卷 16, 期 15, 页码 2771-2787出版社
WILEY
DOI: 10.1002/1878-0261.13264
关键词
apoptosis; cell cycle; CHK1 inhibition; DNA-damage; p27; SKP2
类别
资金
- Medical University of Innsbruck
- Austrian Science Fund
- FWF [I-3271]
- ERC-AdG 'POLICE' [787171]
- DOC82 doc.funds (FWF)
- DOC Fellowship Program of the Austrian Academy of Sciences (oAW)
- European Research Council (ERC) [787171] Funding Source: European Research Council (ERC)
Besides p53 status, the expression levels of SKP2 and p27 may also be important factors in predicting the responsiveness of cancer cells to CHK1 inhibitors.
Checkpoint kinase 1 (CHK1; encoded by CHEK1) is an essential gene that monitors DNA replication fidelity and prevents mitotic entry in the presence of under-replicated DNA or exogenous DNA damage. Cancer cells deficient in p53 tumor suppressor function reportedly develop a strong dependency on CHK1 for proper cell cycle progression and maintenance of genome integrity, sparking interest in developing kinase inhibitors. Pharmacological inhibition of CHK1 triggers B-Cell CLL/Lymphoma 2 (BCL2)-regulated cell death in malignant cells largely independently of p53, and has been suggested to kill p53-deficient cancer cells even more effectively. Next to p53 status, our knowledge about factors predicting cancer cell responsiveness to CHK1 inhibitors is limited. Here, we conducted a genome-wide CRISPR/Cas9-based loss-of-function screen to identify genes defining sensitivity to chemical CHK1 inhibitors. Next to the proapoptotic BCL2 family member, BCL2 Binding Component 3 (BBC3; also known as PUMA), the F-box protein S-phase Kinase-Associated Protein 2 (SKP2) was validated to tune the cellular response to CHK1 inhibition. SKP2 is best known for degradation of the Cyclin-dependent Kinase Inhibitor 1B (CDKN1B; also known as p27), thereby promoting G1-S transition and cell cycle progression in response to mitogens. Loss of SKP2 resulted in the predicted increase in p27 protein levels, coinciding with reduced DNA damage upon CHK1-inhibitor treatment and reduced cell death in S-phase. Conversely, overexpression of SKP2, which consequently results in reduced p27 protein levels, enhanced cell death susceptibility to CHK1 inhibition. We propose that assessing SKP2 and p27 expression levels in human malignancies will help to predict the responsiveness to CHK1-inhibitor treatment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据