Puyol, Marta (2009) Cell cycle and cancer : the role of cyclin dependent kinases in tumourigenesis. (PhD thesis), Kingston University, .
Abstract
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, p27[sup]KiP1 and cyclin 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[sup]+/LSLG12V;RERT[sup]ert/ert strain that carries an endogenous K-Rasoncogene 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[sup]+/LSLG12V;RERT[sup]ert/ert 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. In vivo, Cdk6[sup]-/-;K-ras[sup]+/LSLG12V;RERT[sup]ert/ert and Cdk2[sup]-/-;K-ras[sup]+/LSLG12V;RERT[sup]ert/ert developed the same number of tumours and with the same latency as the parental strain carrying the full complement of Cdk activity. In contrast, Cdk4[sup]-/-;K-ras[sup]+/LSLG12V;RERT[sup]ert/ert mice displayed a significant decrease in the number of adenomas as well as a delay in their progression into adenocarcinomas. In addition, the elimination of Cdk4 after tumour formation results in an important decrease of the tumours. These results, along with those observed in other tumour systems, suggest that Cdk4, but not Cdk2 and Cdk6, may be a target of potential therapeutic interest, at least in K-Ras[sup]G12V driven lung adenocarcinomas.
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