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  • Original Paper
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Loss of the cell cycle inhibitors p21Cip1 and p27Kip1 enhances tumorigenesis in knockout mouse models

Abstract

Events that contribute to tumor formation include mutations in the ras gene and loss or inactivation of cell cycle inhibitors such as p21Cip1 and p27Kip1. In our previous publication, we showed that mice expressing the MMTV/v-Ha-ras transgene developed tumors earlier and at higher multiplicities in the absence than in the presence of p21Cip1. To further evaluate the combinatorial role of genetic alterations and loss of cell cycle inhibitors in tumorigenesis, we performed two companion studies. In the first study, wild type and p21Cip1-null mice were exposed to the chemical carcinogen, urethane. Similar to its effects in v-Ha-ras mice, loss of p21Cip1 accelerated tumor onset and increased tumor multiplicity in urethane-treated mice. Lung tumors were the predominant tumor type in urethane-treated mice regardless of p21Cip1 status. In the second study, tumor formation was monitored in v-Ha-ras mice expressing or lacking p27Kip1. Unlike p21Cip1, the absence of p27Kip1 had no effect on the timing or multiplicity of tumor formation, which was largely restricted to mammary and salivary glands. However, once tumors appeared, they grew faster in p27Kip1-null mice than in p27Kip1-wild type mice. Increases in growth rate were particularly striking for salivary tumors in ras/p27−/− mice. Loss of p21Cip1, on the other hand, had no effect on tumor growth rate in v-Ha-ras mice. Collectively, our data suggest that p21Cip1 suppresses tumor formation elicited by multiple agents and that p21Cip1 and p27Kip1 suppress tumor formation in different ways.

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Acknowledgements

This work was supported by the Cortner-Couch Endowed Chair for Cancer Research (WJ Pledger), NIH Grants CA78038 (SM Sebti and WJ Pledger), CA67360 (WJ Pledger), and CA67771 (SM Sebti), and ACS Grant PF-99-320-01-CNE (RJ Jackson). The authors thank Dr James Roberts and Dr Tyler Jacks for generously providing knockout mice, Nancy Olashaw for manuscript preparation, Sandra Livingston for assistance with immunocytochemistry, and Steve Enkemann for helpful discussions. We also acknowledge the helpful service of the Molecular Imaging Core Laboratory and the Animal Care Core at the Moffitt Cancer Center.

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Correspondence to W Jock Pledger.

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Jackson, R., Adnane, J., Coppola, D. et al. Loss of the cell cycle inhibitors p21Cip1 and p27Kip1 enhances tumorigenesis in knockout mouse models. Oncogene 21, 8486–8497 (2002). https://doi.org/10.1038/sj.onc.1205946

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