Cyclins and CDKS in development and cancer: lessons from genetically modified mice.
From yeast to humans, cell cycle progression and cell division are driven by the sequential activation of a group of serine-threonine kinases called cyclin-dependent kinases (Cdks). Multiple Cdks control the cell cycle in mammals and have been long considered essential for normal proliferation, development and homeostasis. The importance of the Cdk-cyclin complexes in cell proliferation is underscored by the finding that deregulation of the Cdk activity is found in virtually the whole spectrum of human tumors. Recent information from gene-targeted mouse models for the various cyclins and Cdks have made some of the generally accepted concepts of cell cycle regulation to be revised and new and exciting questions to be investigated. Unexpectedly, most of the canonical Cdk-cyclin complexes have turned out to be dispensable for cell proliferation due to a high level of functional redundancy, promiscuity and compensatory mechanisms. As a consequence, a "yeast-like" model where only one Cdk is essential to drive all stages of cell cycle progression is starting to be envisioned for mammalian cells. Moreover, the specific molecular players that drive the cell cycle in mammals seem to be cell-type-specific, and new, non-canonical functions of cyclins and Cdks have been revealed. This review will discuss these new findings and their implications for cancer therapy.
Santamaria
David
D
Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 28029-Madrid, Spain.
Ortega
Sagrario
S
D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism / Q000502:physiology*; D016193:G1 Phase; D016195:G2 Phase; D016147:Genes, Tumor Suppressor; D006801:Humans; D007113:Immunity, Innate; D008540:Meiosis; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D017354:Point Mutation; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D013997:Time Factors
C493957:Cdkn1a protein, mouse; D056741:Cyclin D; D019927:Cyclin E; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases