Targeting the checkpoint kinase Chk1 in cancer therapy.
A paramount objective of the eukaryotic cell division cycle is to overcome numerous internal and external insults to faithfully duplicate the genetic information once per every cycle. This is carried out by elaborate networks of genome surveillance signaling pathways, termed replication checkpoints. Central to replication checkpoints are two protein kinases, the upstream kinase ATR, and its downstream target kinase, Chk1. When the DNA replication process is interrupted, the ATR-Chk1 pathway transmits signals to delay cell cycle progression, and to maintain fork viability so that DNA duplication can resume after the initial damage is corrected. Previous studies showed that replicative stress not only activated Chk1, but also triggered the ubiquitin-dependent destruction of Chk1 in cultured human cells. In a recent study, we identified the F-box protein, Fbx6, as the mediator that regulates Chk1 ubiquitination and degradation in both normally cycling cells and during replication stress. We further showed that expression levels of Chk1 and Fbx6 exhibited an overall inverse correlation in both cultured cancer cell lines and in breast tumor tissues, and that defects in Chk1 degradation, for instance, due to reduced expression of Fbx6, rendered tumor cells resistant to anticancer treatment. Here we highlight those findings and their implications in the replication checkpoint and cellular sensitivity to cancer therapies.
Merry
Callie
C
Department of Pharmacology, Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Fu
Kang
K
Wang
Jingna
J
Yeh
I-Ju
IJ
Zhang
Youwei
Y
D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D004261:DNA Replication; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D011494:Protein Kinases / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism
D018797:Cell Cycle Proteins; C479752:FBXO6 protein, human; D044843:SKP Cullin F-Box Protein Ligases; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases