Cyclin D-dependent kinases, INK4 inhibitors and cancer.
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.
Ortega
Sagrario
S
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Malumbres
Marcos
M
Barbacid
Mariano
M
D000818:Animals; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism; D056742:Cyclin D2; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D011518:Proto-Oncogene Proteins
C080336:CCND2 protein, human; C493956:CDKN1A protein, human; D056742:Cyclin D2; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases