CDK2 and FOXO1: a fork in the road for cell fate decisions.
It has been well established that cyclin-dependent kinases (CDKs) including CDK2 and CDK1 play an essential role in mediating cell-cycle arrest, DNA repair and apoptosis in cells with damaged genomes. Following DNA damage, the function of CDKs is inhibited, and therefore cells are arrested at the G(1), S or G(2)/M phase of the cell-division cycle. It is believed that DNA damage-induced cell cycle arrest is important, because it allows cells to either repair the damage and survive or commit to apoptotic cell death. However, the molecular bases for the two cell fate options are not fully understood. Recently, we provided evidence that CDK2 interacts with and phosphorylates the forkhead transcription factor FOXO1. Importantly, activated CDK2 inhibits the pro-apoptotic function of FOXO1. However, in the presence of high levels of double-strand breaks (DSBs) the CDK2-mediated inhibition of FOXO1 is abrogated due to the ablation of CDK2 activity, and therefore the anti-apoptotic function of FOXO1 is restored. Thus, CDK2 silencing-dependent activation of FOXO1 represents a new mechanism that links DNA strand breakage to cell death.
Huang
Haojie
H
The Cancer Center and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
Tindall
Donald J
DJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000502:physiology*; D004249:DNA Damage / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D018816:Genes, cdc / Q000502:physiology; D006801:Humans; D008954:Models, Biological
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2