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Cyclin D-dependent kinases, INK4 inhibitors and cancer
Sagrario Ortega1, Marcos Malumbres, Mariano Barbacid
1Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Abstract:
The Cyclin D-Cdk4,6/INK4/Rb/E2F pathway plays a key role in controlling cell growth by integrating multiple mitogenic and antimitogenic stimuli. The components of this pathway are gene families with a high level of structural and functional redundancy and are expressed in an overlapping fashion in most tissues and cell types. Using classical transgenic technology as well as gene-targeting in ES cells, a series of mouse models have been developed to study the in vivo function of individual components of this pathway in both normal homeostasis and tumor development. These models have proven to be useful to define specific as well as redundant roles among members of these cell cycle regulatory gene families. This pathway is deregulated in the vast majority of human tumors by genetic and epigenetic alterations that target at least some of its key members such as Cyclin D1, Cdk4, INK4a and INK4b, pRb etc. As a consequence, some of these molecules are currently being considered as targets for cancer therapy, and several novel molecules, such as Cdk inhibitors, are under development as potential anti-cancer drugs.
Insights
Mouse models reveal roles of cell cycle regulators in growth and cancer. These studies define specific and redundant functions within the Cyclin D-Cdk4,6/INK4/Rb/E2F pathway, informing cancer therapy development.
Area of Science:
- Cell Biology
- Molecular Oncology
- Genetics
Background:
- The Cyclin D-Cdk4,6/INK4/Rb/E2F pathway is crucial for cell cycle control, integrating growth signals.
- Pathway components exhibit functional redundancy and overlapping expression across tissues.
Purpose of the Study:
- To investigate the in vivo functions of individual cell cycle pathway components.
- To elucidate the roles of these components in normal tissue homeostasis and tumor development.
Main Methods:
- Utilized classical transgenic technology in mice.
- Employed gene-targeting in embryonic stem (ES) cells to create mouse models.
Main Results:
- Established mouse models to define specific and redundant functions of cell cycle regulatory gene families.
- Demonstrated the utility of these models for studying pathway component roles in vivo.
Conclusions:
- The Cyclin D-Cdk4,6/INK4/Rb/E2F pathway is frequently deregulated in human tumors.
- Pathway components are potential targets for novel anti-cancer drugs, such as Cdk inhibitors.