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Regulation of the cell cycle by CDK inhibitors

  • Chapter
Cell Cycle Control

Part of the book series: Results and Problems in Cell Differentiation ((RESULTS,volume 22))

Abstract

There are at least four possible ways in which inhibitors of cyclin-dependent kinases (CDKs) might regulate cell cycle progression (Fig. 1). First, they might determine the duration of G1 phase by setting a threshold above which G1 CDK activity must accumulate before initiation of S-phase. In this threshold role, steady-state levels of CDK inhibitors (CKIs) counteract the temporal accumulation of G1 cyclin/CDK complexes. Second, they might act as checkpoints inducing cell cycle arrest transiently when genomic fidelity is threatened. Chromosome damage or inappropriate segregation of chromosomes may induce cell cycle arrest and initiate DNA repair mechanisms or apoptotic programs. Third, CKIs might allow expedient withdrawal of cells from the cell cycle and a concomitant change in cell fate. In some cases, CKIs might not only regulate the withdrawal from the cell cycle but also affect lineage-specific functions. Fourth, they might function as a gatekeeper of quiescence, keeping the GO cell

Four transitions in the cell cycle that can be controlled, in part, by the CKI. The phases of the cell cycle are indicated (G1, S, G2, M, and G0) and the G1 cyclin/CDK complexes are placed according to the time of their first activities during the mitotic cell cycle. The four transitions are the passage of a cell to DNA replication directly from mitosis (1), any time in the cell cycle that has the ability to respond to threats to genomic fidelity (2), during withdrawal from the cell cycle (3), and during re-entry into the cell cycle (4)

from inappropriately resuming proliferation. In some cases, tumors arise from well differentiated and non-mitotic cells that inexplicably return to the cell cycle. Over the last 5 years, biochemical, cellular, and molecular analyses of CKIs have combined with genetic analysis of mutant mice deficient in each CKI to address these possible functions. Our current knowledge of the role of CKI in these decisions and speculations about their roles in developmentally regulated cell cycles are discussed below.

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  1. Program in Molecular Biology, Memorial Sloan-Kettering Cancer Center, RRL 917D, Box 207, 1275 York Avenue, New York, New York, 10021, USA

    A. Koff

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  1. T. J. Soos
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  2. M. Park
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  1. Department of Pathology, MSB 548, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA

    Michele Pagano

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Soos, T.J., Park, M., Kiyokawa, H., Koff, A. (1998). Regulation of the cell cycle by CDK inhibitors. In: Pagano, M. (eds) Cell Cycle Control. Results and Problems in Cell Differentiation, vol 22. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-69686-5_5

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