Driving the cell cycle to cancer.
Cell cycle progression requires the co-ordinated activation of several kinases, some of which are activated upon the binding of a cyclin subunit. At least four of these so-called cyclin-dependent kinases, namely Cdk4, Cdk6, Cdk2 and Cdk1, have specific roles at particular stages of the cell cycle, including passage through the various cell cycle transitions and the response to specific checkpoints. Not surprisingly, most human tumors carry mutations that deregulate at least one of these kinases. To analyze their specific role in vivo, we are generating strains of gene-targeted mice carrying either activated or defective alleles of these Cdks. As an example, Cdk4 expression appears to be expendable in most cell types since mice lacking Cdk4 are viable. Yet, Cdk4 mutant mice are smaller in size and infertile (only partial infertility in males). In addition, Cdk4 defective mice develop insulin dependent diabetes early in life. However, the importance of these Cdks in tumor cell cycles is underscored by the phenotype of knock in mice where the normal Cdk4 gene has been replaced by a Cdk4 R24C (insensitive to INK inhibitors) mutant. These animals develop a wide spectrum of spontaneous tumors and are highly susceptible to specific carcinogenic treatments. These models are being used now to understand how deregulation of these Cdks leads to cancer development and will be a valuable tool to design and validate new therapeutic strategies against tumour development.
Malumbres
Marcos
M
Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain. marcos.malumbres@cnio.es
Hunt
Sarah L
SL
Sotillo
Rocío
R
Martín
Javier
J
Odajima
Jun
J
Martín
Alberto
A
Dubus
Pierre
P
Ortega
Sagrario
S
Barbacid
Mariano
M
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002453:Cell Cycle; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D013997:Time Factors
D011518:Proto-Oncogene Proteins; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases