Aberrant activation of cyclin A-CDK induces G2/M-phase checkpoint in human cells

被引：11

作者：

Akaike, Yasunori ^{[1
]}

Chibazakura, Taku ^{[1
]}

机构：

[1] Tokyo Univ Agr, Dept Biosci, Tokyo, Japan

来源：

CELL CYCLE | 2020年 / 19卷 / 01期

关键词：

Cyclin A-CDK; G2; M-phase checkpoint; adenovirus E1A; PROTEIN-KINASE; PROTEOLYSIS; BINDING; EXIT;

D O I：

10.1080/15384101.2019.1693119

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Cyclin A-cyclin dependent kinase (CDK) activity is regulated by cyclin A proteolysis and CDK inhibitors (CKIs) during M and G1 phases. Our previous work has shown that constitutive activation of cyclin A-CDK in mouse somatic cells, by ectopic expression of stabilized human cyclin A2 (lacking the destruction box: CycA Delta 80) in triple CKI (p21, p27, and p107)-knocked-out mouse embryonic fibroblasts, induces rapid tetraploidization. However, effects of such cyclin A-CDK hyperactivation in human cells have been unknown. Here, we show hyperactivity of cyclin A-CDK induces G2/M-phase arrest in human cell lines with relatively low expression of p21 and p27. Moreover, adenovirus E1A protein promoted CycA Delta 80-derived G2/M-phase arrest by increasing the amount of cyclin A and cyclin A-CDK2 complex. This response was suppressed by an addition of ATR or Chk1 inhibitor. The amount of repressive phosphorylation of CDK1 at tyrosine 15 (Y15) was decreased by Chk1 inhibitor treatment. Moreover, we observed that co-expressing CDK1AF mutant, which is resistant to the repressive phosphorylation at threonine 14 and Y15, or cdc25A, which dephosphorylates CDK1 at Y15, suppressed the G2/M-phase arrest by CycA Delta 80 with E1A. These results suggest that G2/M-phase arrest in human cells by hyperactivity of cyclin A-CDK2 is caused by repression of CDK1 via the cell cycle checkpoint ATR-Chk1 pathway.

引用

页码：84 / 96

页数：13

共 23 条

[1] Cdk2 strengthens the intra-S checkpoint and counteracts cell cycle exit induced by DNA damage [J].