Abstract
Deregulation of the G1-S transition of the cell cycle is a common feature of human cancer. Tumor-associated alterations in this process frequently affect cyclin-dependent kinases (Cdk), their regulators (cyclins, INK4 inhibitors, or p27Kip1), and their substrates (retinoblastoma protein). Although these proteins are generally thought to act in a linear pathway, mutations in different components frequently cooperate in tumor development. Using gene-targeted mouse models, we report in this article that Cdk4 resistance to INK4 inhibitors, due to the Cdk4 R24C mutation, strongly cooperates with p27(Kip1) deficiency in tumor development. No such cooperation is observed between Cdk4 R24C and p18(INK4c) absence, suggesting that the only function of p18INK4c is inhibiting Cdk4 in this model. Cdk4(R/R) knock in mice, which express the Cdk4 R24C mutant protein, develop pituitary tumors with complete penetrance and short latency in a p27Kip1-/- or p27Kip1+/- background. We have investigated whether this tumor model could be useful to assess the therapeutic activity of cell cycle inhibitors. We show here that exposure to flavopiridol, a wide-spectrum Cdk inhibitor, significantly delays tumor progression and leads to tumor-free survival in a significant percentage of treated mice. These data suggest that genetically engineered tumor models involving key cell cycle regulators are a valuable tool to evaluate drugs with potential therapeutic benefit in human cancer.
Highlights
Cell cycle progression relies on the activation of cyclindependent kinases (Cdk), which successively act in G1 to initiate S phase and in G2 to initiate mitosis
D-type cyclins and Cdk4 and Cdk6, without inhibiting Cdk2 complexes [8]. This hypothesis is supported by a mouse model showing that p27+/- mammary epithelium is more susceptible to oncogene-induced tumorigenesis than p27À/À mammary glands at least in cooperation with particular oncogenes [38]. Apart from this particular case, p27Kip1 and PTEN deficiency cooperate in tumor development and p27Kip1-null mice are more susceptible to the simplistic scheme of the pRb pathway places all the G1-S cyclin-dependent kinases (Cdk) and their regulators upstream of pRb, there is genetic evidence suggesting that the situation is not as simple. p27Kip1 depletion cooperates with pRb inactivation or p18INK4c absence in tumor development [17, 34]
Double Cdk4R/R;p18À/À mutant mice seem to display an increased viability at least between weeks 50 and 70 when compared with Cdk4R/R;p18+/+ mice (Fig. 2A). These results could suggest that p18INK4c absence might be protecting mice from the Cdk4 R24C mutation, the reduced number of Cdk4R/R;p18À/À mice (n = 8) limit the relevance of these data
Summary
Cell cycle progression relies on the activation of cyclindependent kinases (Cdk), which successively act in G1 to initiate S phase and in G2 to initiate mitosis. Dtype cyclins are induced and bind to and activate the cell cycle kinases Cdk and Cdk Cyclin D-Cdk4/6 complexes phosphorylate and partially inactivate pRb, allowing the expression of some E2F-target genes such as the gene encoding cyclin E. Induction of cyclin E, in turn, allows the activation of Cdk, which is able to further phosphorylate and completely inactivate pRb, releasing a massive transcription process that results in the expression of genes required for DNA replication and mitosis. Cdk is able to bind A-type cyclins during S phase, Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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