Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis

Cyclin D1 is a multifunctional protein that activates CDK4 and CDK6, titrates Cip/Kip CDK inhibitors to increase CDK2 activity, and modulates the function of certain transcription factors. To specifically test the importance of cyclin D1-associated kinase activity, we generated “knockin” mice expres...

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Bibliographic Details
Published in:Cancer cell 2006, Vol.9 (1), p.13-22
Main Authors: Landis, Mark W., Pawlyk, Basil S., Li, Tiansen, Sicinski, Piotr, Hinds, Philip W.
Format: Article
Language:English
Subjects:
Animals
CELLCYCLE
Cyclin D1 - genetics
Cyclin D1 - metabolism
Cyclin-Dependent Kinase 4 - genetics
Cyclin-Dependent Kinase 4 - metabolism
Cyclin-Dependent Kinase 6 - genetics
Cyclin-Dependent Kinase 6 - metabolism
Enzyme Activation
Female
Genes, erbB-2
Mammary Glands, Animal - enzymology
Mammary Glands, Animal - growth & development
Mammary Neoplasms, Experimental - metabolism
Mammary Neoplasms, Experimental - pathology
Mice
Mice, Mutant Strains
Mutation
Protein Binding
Retina - enzymology
Retina - growth & development
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Summary:Cyclin D1 is a multifunctional protein that activates CDK4 and CDK6, titrates Cip/Kip CDK inhibitors to increase CDK2 activity, and modulates the function of certain transcription factors. To specifically test the importance of cyclin D1-associated kinase activity, we generated “knockin” mice expressing mutant cyclin D1 deficient in activating CDK4/6. The development of several cyclin D1-dependent compartments, including mammary glands, proceeds relatively normally in these animals, demonstrating that cyclin D1-associated kinase activity is largely dispensable for development of these tissues. Strikingly, knockin mice were resistant to breast cancers initiated by ErbB-2. These results demonstrate a differential requirement for cyclin D1-CDK4/6 kinase activity in development versus tumorigenesis and strongly support cyclin D1-dependent kinase activity as a specific therapeutic target in breast cancer.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2005.12.019