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Cell Cycle Regulation pp 271–328Cite as

Mouse Models of Cell Cycle Regulators: New Paradigms

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Part of the book series: Results and Problems in Cell Differentiation ((RESULTS,volume 42))

Abstract

In yeast, a single cyclin-dependent kinase (Cdk) is able to regulate diverse cell cycle transitions (S and M phases) by associating with multiple stage-specific cyclins. The evolution of multicellular organisms brought additional layers of cell cycle regulation in the form of numerous Cdks, cyclins and Cdk inhibitors to reflect the higher levels of organismal complexity. Our current knowledge about the mammalian cell cycle emerged from early experiments using human and rodent cell lines, from which we built the current textbook model of cell cycle regulation. In this model, the functions of different cyclin/Cdk complexes were thought to be specific for each cell cycle phase. In the last decade, studies using genetically engineered mice in which cell cycle regulators were targeted revealed many surprises. We discovered the in vivo functions of cell cycle proteins within the context of a living animal and whether they are essential for animal development. In this review, we discuss first the textbook model of cell cycle regulation, followed by a global overview of data obtained from different mouse models. We describe the similarities and differences between the phenotypes of different mouse models including embryonic lethality, sterility, hematopoietic, pancreatic, and placental defects. We also describe the role of key cell cycle regulators in the development of tumors in mice, and the implications of these data for human cancer. Furthermore, animal models in which two or more genes are ablated revealed which cell cycle regulators interact genetically and functionally complement each other. We discuss for example the interaction of cyclin D1 and p27 and the compensation of Cdk2 by Cdc2. We also focus on new functions discovered for certain cell cycle regulators such as the regulation of S phase by Cdc2 and the role of p27 in regulating cell migration. Finally, we conclude the chapter by discussing the limitations of animal models and to what extent can the recent findings be reconciled with the past work to come up with a new model for cell cycle regulation with high levels of redundancy among the molecular players.

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Acknowledgments

We thank Cyril Berthet for discussion, support, and communication of unpublished results. We are grateful to all members of the Kaldis lab for their support. We are also indebted to Nancy Jenkins and Neal Copeland and all members of the Mouse Cancer Genetics Program, at the NCI-Frederick for their thoughtful discussions and continuous support. Our thanks extend also to Hiroaki Kiyokawa, Northwestern, and Michele Pagano, NYU, for support and discussions. The work in our laboratory was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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  1. National Cancer Institute, Mouse Cancer Genetics Program, NCI-Frederick, Bldg. 560/22-56, 1050 Boyles Street, 21702-1201, Frederick, MD, USA

    Eiman Aleem & Philipp Kaldis

  2. Department of Zoology, Faculty of Science, University of Alexandria, Alexandria, Egypt

    Eiman Aleem

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Aleem, E., Kaldis, P. Mouse Models of Cell Cycle Regulators: New Paradigms. In: Kaldis, P. (eds) Cell Cycle Regulation. Results and Problems in Cell Differentiation, vol 42. Springer, Berlin, Heidelberg. https://doi.org/10.1007/400_023

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