The consequence of p53 overexpression for liver tumor development and the response of transformed murine hepatocytes to genotoxic agents

Abstract

To analyse the eect of p53 on liver tumor development, we generated transgenic mice overexpressing wild-type p53 in the liver and crossed them with transgenic mice in which the expression of the SV40 large T antigen (TAg) induces hepatic tumors. Remarkably, whereas preneoplastic TAg liver exhibited anisocaryosis and anisocytosis, TAg/p53 liver never presented any dysplastic cells. Moreover, whereas expression of p53 did not aect hepatic development, its constitutive expression in tumorigenic livers resulted in a signi®cantly enhanced apoptosis once nodules had appeared. In contrast, p53 overexpression did not modify the elevated proliferation of TAg-transformed hepatocytes and had no eect on hepatocarcinoma progression. In vitro analysis of primary hepatocytes exposed to various genotoxic agents showed that p53 failed to sensitize normal or TAgtransformed hepatocytes to apoptosis, except when high doses of doxorubicin, UV-B and UV-C radiation were used. Our results con®rmed that the hepatocyte cell type is very resistant to genotoxic agents and showed that constitutive expression of p53 failed to improve their responsiveness. In addition, our results showed that suppression of dysplastic cells, probably by restoring normal cytokinesis and karyokinesis, and enhancement of apoptosis by means of p53 overexpression were insucient to counteract or delay the TAg-induced liver tumoral progression.

Retinoic Acid Increases the Expression of p53 and Proapoptotic Caspases and Sensitizes Keratinocytes to Apoptosis

“…The fact that despite the strong up-regulation of p53 and proapoptotic caspases no spontaneous apoptosis of retinoid-treated KCs was observed in monolayer cultures is in agreement with the previous observations that even strong overexpression of caspases or p53 does not necessarily cause apoptosis but rather sensitizes cells to apoptotic cell death (19,20). This notion is supported at the molecular level by the observation that in the absence of apoptotic stimuli, the p53 target gene MDM2 is up-regulated, whereas protein accumulation of p53 and strong up-regulation of the proapoptotic target gene Noxa were present only after additional exposure to UVB.…”

“…Mutations of p53, as in Li Fraumeni syndrome, and deletion of p53 in experimental animals predispose to the development of neoplastic tumors (17,18). Overexpression of p53 by itself does not induce apoptosis; rather, it lowers the apoptotic threshold in response to DNA damage (19,20). Importantly, experimental evidence indicates that the proapoptotic activity and the chemopreventive effect of retinoids depend on the presence of wild-type p53 (21)(22)(23).…”

Chromosomal Instability and Supernumerary Centrosomes Represent Precursor Defects in a Mouse Model of T-Cell Lymphoma

“…Of note, in the p53À/ÀLck-Bax38/1 mice in the 3-to 6-week age group, two of the eight mice had aneuploidy below the 10% cutoff. These data again suggest that the phenotype is age dependent even in the absence of p53 and supports a model that loss of p53 exacerbates CIN, perhaps by decreased apoptosis of aneuploid cells (33,34).…”

Cell death by mitotic catastrophe: a molecular definition

“…Thus, the inactivation of p53 by SV40 transgenes can lead to tetraploidy in the mouse pancreas (Ramel et al, 1995) as well as to cytological abnormalities (anisokaryosis and anisocytosis) in the mouse liver (Gillet et al, 2000). This latter effect is prevented by the overexpression of transgenic wild-type p53 (Gillet et al, 2000).…”