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D-type Cyclins and Cancer pp 1–26Cite as

The D-Type Cyclins: A Historical Perspective

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Part of the book series: Current Cancer Research ((CUCR))

Abstract

D-type cyclins integrate mitogen-dependent signals to enforce progression through the first gap phase (G1) of the cell division cycle. In simplest terms, three mammalian D-type cyclins (D1, D2, and D3), induced in a cell lineage-specific fashion in response to extracellular signals, interact with two cyclin-dependent kinases (CDK4 and CDK6) to form holoenzyme complexes that phosphorylate the retinoblastoma protein (RB). In turn, RB phosphorylation, reinforced by other CDKs expressed later in G1 phase, inactivates the suppressive effects of RB on transcription factors that induce genes required for DNA replication. All steps in the life history of individual D-type cyclins, including their transcriptional induction, translation, assembly with CDK4 and CDK6, and their rapid turnover via ubiquitin-mediated proteolysis, are governed by mitogen signaling. Hence, progression through the G1 phase of the mammalian cell cycle is tied to extracellular signals that ultimately influence cell division. Analysis of phenotypes of mice lacking D cyclins has highlighted their individual and combinatorial lineage-specific activities during mammalian development. The genes encoding D-type cyclins and their dependent kinases, CDK4 and CDK6, are proto-oncogenes implicated in many forms of cancer. Genetic or biochemical disruption of cyclin D-dependent CDK signaling can restrain cancer development and progression. Here, we highlight the founding discoveries.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Charles J. Sherr

  2. Department of Genetics, Harvard Medical School, and Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA

    Peter Sicinski

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  1. Charles J. Sherr
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Correspondence to Charles J. Sherr .

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  1. Tufts University School of Medicine, Boston, Massachusetts, USA

    Philip W. Hinds

  2. University of Talca Medical School, Talca, Chile

    Nelson E. Brown

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Sherr, C.J., Sicinski, P. (2018). The D-Type Cyclins: A Historical Perspective. In: Hinds, P., Brown, N. (eds) D-type Cyclins and Cancer. Current Cancer Research. Springer, Cham. https://doi.org/10.1007/978-3-319-64451-6_1

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