PerspectiveCANCER

Surprising regulation of cell cycle entry

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Science  13 Dec 2019:
Vol. 366, Issue 6471, pp. 1315-1316
DOI: 10.1126/science.aaz4043

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Summary

The activities of cyclin-dependent kinases (CDKs), regulated primarily by the periodic expression of their cyclin binding partners, temporally order sequential cell cycle transitions through G1, S phase, G2, and mitosis. In mammalian cells, regulators of G1 transit include three D-type cyclins, as well as CDK4 and CDK6, and the CDK inhibitory proteins, p21 and p27 (1). In response to mitogens, individual D-type cyclins assemble with CDK4 or CDK6 and, paradoxically, with the p21 or p27 “inhibitors” to yield active higher-order holoenzymes that drive G1 progression and prime cells to enter S phase and begin DNA replication (2). On page 1330 of this issue, Guiley et al. (3) report the crystal structures of trimeric complexes containing cyclin D1, CDK4, and either p27 or p21 and reveal that active trimers containing tyrosine-phosphorylated p27 are surprisingly refractory to the U. S. Food and Drug Administration (FDA)–approved CDK4/6 inhibitors that are used to treat hormone-dependent breast cancer.

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