Altered G1 signaling order and commitment point in cells proliferating without CDK4/6 activity

Chad Liu, Yumi Konagaya, Mingyu Chung, Leighton H. Daigh, Yilin Fan, Hee Won Yang, Kenta Terai, Michiyuki Matsuda and Tobias Meyer ()
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Chad Liu: Stanford Medicine
Yumi Konagaya: Stanford Medicine
Mingyu Chung: Stanford Medicine
Leighton H. Daigh: Stanford Medicine
Yilin Fan: Stanford Medicine
Hee Won Yang: Stanford Medicine
Kenta Terai: Kyoto University
Michiyuki Matsuda: Kyoto University
Tobias Meyer: Stanford Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Cell-cycle entry relies on an orderly progression of signaling events. To start, cells first activate the kinase cyclin D-CDK4/6, which leads to eventual inactivation of the retinoblastoma protein Rb. Hours later, cells inactivate APC/CCDH1 and cross the final commitment point. However, many cells with genetically deleted cyclin Ds, which activate and confer specificity to CDK4/6, can compensate and proliferate. Despite its importance in cancer, how this entry mechanism operates remains poorly characterized, and whether cells use this path under normal conditions remains unknown. Here, using single-cell microscopy, we demonstrate that cells with acutely inhibited CDK4/6 enter the cell cycle with a slowed and fluctuating cyclin E-CDK2 activity increase. Surprisingly, with low CDK4/6 activity, the order of APC/CCDH1 and Rb inactivation is reversed in both cell lines and wild-type mice. Finally, we show that as a consequence of this signaling inversion, Rb inactivation replaces APC/CCDH1 inactivation as the point of no return. Together, we elucidate the molecular steps that enable cell-cycle entry without CDK4/6 activity. Our findings not only have implications in cancer resistance, but also reveal temporal plasticity underlying the G1 regulatory circuit.

Date: 2020
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DOI: 10.1038/s41467-020-18966-9

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