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The D-Type Cyclins: A Historical Perspective

  • Charles J. SherrEmail author
  • Peter Sicinski
Chapter
Part of the Current Cancer Research book series (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.

Keywords

Cell cycle G1-phase progression CDK4 CDK6 Retinoblastoma protein (RB) CDKN2A p16INK4a RB pathway Cancer Palbociclib 

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Howard Hughes Medical Institute, Department of Tumor Cell BiologySt. Jude Children’s Research HospitalMemphisUSA
  2. 2.Department of Genetics, Harvard Medical School, and Department of Cancer BiologyDana Farber Cancer InstituteBostonUSA

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