Cooperativity of p19ARF, Mdm2, and p53 in murine tumorigenesis

Abstract

The p19ARF gene product responds to oncogenic stresses by interfering with the inhibitory effects of Mdm2 on p53, thus enhancing p53 activity and its antiproliferative functions. The absence of p19 ARF in the mouse leads to early tumor susceptibility, presumably in part due to decreased p53 activity. To examine the tumorigenic cooperativity of p19 ARF , Mdm2, and p53 in vivo, p19 ARF -deficient mice were crossed first to p53-deficient mice and then to Mdm2 transgenic mice. The progeny were monitored for tumors. Cooperativity between p19 ARF and p53 deficiencies in accelerating tumor formation was observed for most genotypes except p53À/À p19 ARF À/À mice. p53À/À p19 ARF À/À mice had a tumor incidence similar to p53À/À mice. In this context, tumor suppression by ARF appears to be primarily p53 dependent. The majority of the p19 ARF þ /À tumors deleted the wildtype p19 ARF allele, in agreement with the previous studies, suggesting that p19 ARF is a classic 'two hit' tumor suppressor. In a p53 þ /À background, however, all p19 ARF þ /À tumors retained a wildtype ARF allele and most also retained wildtype p53. In the second cross between p19 ARF -deficient and Mdm2 transgenic mice, cooperativity in tumor incidence between Mdm2 overexpression and ARF deficiency was observed, consistent with the role of p19 ARF in negatively regulating Mdm2 activity. These experiments further demonstrate in vivo the inter-relationships of the p19 ARF -Mdm2-p53 signaling axis in tumor suppression.

Decreased Mdm2 expression inhibits tumor development induced by loss of ARF

“…There was a similar frequency of lymphomas, sarcomas, and carcinomas that emerged in both genotypes of mice (Table 2). Lymphoma and sarcoma were the most frequent tumor types observed, which is consistent with previous publications (Kamijo et al, 1997(Kamijo et al, , 1999Eischen et al, 2002;Moore et al, 2003). The lymphomas identified in both genotypes were B-cell, T-cell, or of indeterminate lineage.…”

“…These results open the door for new treatment regiments that target Mdm2 in tumors that lack ARF expression. Tumorigenesis in ARF À/À mice has been reported to be in part independent of p53 (Weber et al, 2000;Moore et al, 2003). Similarly, Mdm2 can function in a p53-dependent and a p53-independent manner (reviewed in Ganguli and Wasylyk, 2003).…”

Induction of the adenoma-carcinoma progression and Cdc25A-B phosphatases by the trefoil factor TFF1 in human colon epithelial cells

“…Moreover, TFF1 overexpression induced resistance to apoptosis, as shown here by PARP cleavage and persistence of the two anti-apoptotic proteins Bcl-2 and MDM2. MDM2 is also found overexpressed or amplified in a wide variety of sarcoma, leukemia and other cancers, and controls many functions linked to cell proliferation and apoptosis, a situation associated with a poor prognosis (Moore et al, 2003;Onel and Cordon-Cardo, 2004;Zhang et al, 2004). A positive correlation between MDM2 and Bcl-2 levels has been identified during malignant transformation (Soufla et al, 2005).…”

Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development

“…These results would suggest that ARF deletion or p53 mutation and Mdm2 overexpression are two separate selected events during tumor development that independently contribute to lymphomagenesis. Indeed, a deficiency in ARF and overexpression of Mdm2 has been shown by others to be capable of accelerating tumor development (Moore et al, 2003). This decreased tumor latency in ARF-null/Mdm2-overexpressing mice is purported to be independent of p53, as loss of both p53 and ARF did not alter tumor latency Moore et al, 2003).…”

“…Several studies implicate the cooperation of ARF loss and Mdm2 overexpression on cell cycle and tumorigenesis (Lundgren et al, 1997;Eischen et al, 1999;Foster and Lozano, 2002;Alt et al, 2003;Moore et al, 2003), and that this can occur in a p53-independent manner. Specifically, defects in mammary gland development are accentuated in ARF-null mice overexpressing Mdm2 in breast epithelial cells (Foster and Lozano, 2002).…”