Cell cycle and cancer : the role of cyclin dependent kinases in tumourigenesis
Most human cancers carry mutations in cell cycle regulators that result in deregulated Cdk activity, which can either be amplification of the cyclins, elimination of the Cdk inhibitors or mutations in the Cdks. These modifications have a high prognostic value. Cdk2 activity has been shown to be upregulated in different kind of tumours (mammary and prostate carcinomas, and lymphomas) due to the mutation of its regulators, p27KiP1 and cyc/in E; and this alteration has a high prognostic value. Moreover, an insensible INK4 point mutation in Cdk4 has been described in human melanomas. To evaluate the importance of Cdks in neoplastic development, the loci encoding Cdk4, Cdk6 and Cdk2 were ablated to study the effect of Cdk deficiency in tumour development. To this end, the corresponding Cdk knock out mice were crossed with the K_Ras+/LSLG12V;RERertert strain that carries an endogenous K-Ras oncogene whose expression is dependent on Cre-mediated recombination. Postnatal expression of this oncogene leads to the development of lung adenomas and adenocarcinomas. Primary MEFs derived from K- Ras+ILSLG12V;RERrrtlert embryos lacking either Cdk4, Cdk6 or Cdk2 displayed decreased proliferation in culture and prevented the growth in low serum condition. However, no obvious differences were detected in immortal MEFs regardless of the missing Cdk.