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- W2891992691 abstract "Cell cycle regulation, especially faithful DNA replication and mitosis, are crucial to maintain genome stability. Cyclin-dependent kinase (CDK)/cyclin complexes drive most processes in cellular proliferation. In response to DNA damage, cell cycle surveillance mechanisms enable normal cells to arrest and undergo repair processes. Perturbations in genomic stability can lead to tumor development and suggest that cell cycle regulators could be effective targets in anticancer therapy. However, many clinical trials ended in failure due to off-target effects of the inhibitors used. Here, we investigate in vivo the importance of WEE1- and MYT1-dependent inhibitory phosphorylation of mammalian CDK1. We generated Cdk1AF knockin mice, in which two inhibitory phosphorylation sites are replaced by the non-phosphorylatable amino acids T14A/Y15F. We uncovered that monoallelic expression of CDK1AF is early embryonic lethal in mice and induces S phase arrest accompanied by γH2AX and DNA damage checkpoint activation in mouse embryonic fibroblasts (MEFs). The chromosomal fragmentation in Cdk1AF MEFs does not rely on CDK2 and is partly caused by premature activation of MUS81-SLX4 structure-specific endonuclease complexes, as well as untimely onset of chromosome condensation followed by nuclear lamina disassembly. We provide evidence that tumor development in liver expressing CDK1AF is inhibited. Interestingly, the regulatory mechanisms that impede cell proliferation in CDK1AF expressing cells differ partially from the actions of the WEE1 inhibitor, MK-1775, with p53 expression determining the sensitivity of cells to the drug response. Thus, our work highlights the importance of improved therapeutic strategies for patients with various cancer types and may explain why some patients respond better to WEE1 inhibitors." @default.
- W2891992691 created "2018-09-27" @default.
- W2891992691 creator A5002638060 @default.
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- W2891992691 date "2018-09-06" @default.
- W2891992691 modified "2023-10-01" @default.
- W2891992691 title "Premature activation of Cdk1 leads to mitotic events in S phase and embryonic lethality" @default.
- W2891992691 cites W1481748141 @default.
- W2891992691 cites W1509901905 @default.
- W2891992691 cites W1519389973 @default.
- W2891992691 cites W1542213143 @default.
- W2891992691 cites W1542558659 @default.
- W2891992691 cites W1544564404 @default.
- W2891992691 cites W1544874562 @default.
- W2891992691 cites W1547945395 @default.
- W2891992691 cites W1553801822 @default.
- W2891992691 cites W1901442544 @default.
- W2891992691 cites W1939611276 @default.
- W2891992691 cites W1966870645 @default.
- W2891992691 cites W1968144640 @default.
- W2891992691 cites W1971017541 @default.
- W2891992691 cites W1973461983 @default.
- W2891992691 cites W1975667412 @default.
- W2891992691 cites W1977541278 @default.
- W2891992691 cites W1978331091 @default.
- W2891992691 cites W1979341555 @default.
- W2891992691 cites W1981525849 @default.
- W2891992691 cites W1990906839 @default.
- W2891992691 cites W1991494214 @default.
- W2891992691 cites W1994107958 @default.
- W2891992691 cites W1995246974 @default.
- W2891992691 cites W1998323196 @default.
- W2891992691 cites W1998756818 @default.
- W2891992691 cites W1999796994 @default.
- W2891992691 cites W2003245647 @default.
- W2891992691 cites W2003381961 @default.
- W2891992691 cites W2009389356 @default.
- W2891992691 cites W2013714072 @default.
- W2891992691 cites W2018782003 @default.
- W2891992691 cites W2019918282 @default.
- W2891992691 cites W2020391983 @default.
- W2891992691 cites W2020520526 @default.
- W2891992691 cites W2021536045 @default.
- W2891992691 cites W2021717224 @default.
- W2891992691 cites W2022211851 @default.
- W2891992691 cites W2023942118 @default.
- W2891992691 cites W2025073354 @default.
- W2891992691 cites W2025679668 @default.
- W2891992691 cites W2028966473 @default.
- W2891992691 cites W2031167624 @default.
- W2891992691 cites W2031576542 @default.
- W2891992691 cites W2038143768 @default.
- W2891992691 cites W2042742511 @default.
- W2891992691 cites W2044267903 @default.
- W2891992691 cites W2045069136 @default.
- W2891992691 cites W2045563337 @default.
- W2891992691 cites W2050838528 @default.
- W2891992691 cites W2051075276 @default.
- W2891992691 cites W2051928958 @default.
- W2891992691 cites W2055222724 @default.
- W2891992691 cites W2059155490 @default.
- W2891992691 cites W2059594509 @default.
- W2891992691 cites W2060636149 @default.
- W2891992691 cites W2061066809 @default.
- W2891992691 cites W2061730009 @default.
- W2891992691 cites W2063979868 @default.
- W2891992691 cites W2064554826 @default.
- W2891992691 cites W2065634301 @default.
- W2891992691 cites W2065971145 @default.
- W2891992691 cites W2066188648 @default.
- W2891992691 cites W2066793571 @default.
- W2891992691 cites W2070061120 @default.
- W2891992691 cites W2073031672 @default.
- W2891992691 cites W2075707444 @default.
- W2891992691 cites W2077457339 @default.
- W2891992691 cites W2077890614 @default.
- W2891992691 cites W2079019214 @default.
- W2891992691 cites W2080125477 @default.
- W2891992691 cites W2080401826 @default.
- W2891992691 cites W2082447947 @default.
- W2891992691 cites W2085365618 @default.
- W2891992691 cites W2088120691 @default.
- W2891992691 cites W2089218510 @default.
- W2891992691 cites W2092904031 @default.
- W2891992691 cites W2093320357 @default.
- W2891992691 cites W2093442957 @default.
- W2891992691 cites W2096293110 @default.
- W2891992691 cites W2097130397 @default.