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

2002; Springer Nature; Volume: 21; Issue: 55 Linguagem: Inglês

10.1038/sj.onc.1205946

1476-5594

Rosalind J. Jackson, Jalila Adnane, Domenico Coppola, Alan Cantor, Saı̈d M. Sebti, W Jock Pledger,

Cancer, Hypoxia, and Metabolism

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.