Induction of Invasive Mouse Skin Carcinomas in Transgenic Mice with Mutations in Both H-ras and p53

Abstract

Synergistic interaction between H-ras and p53 were systematically examined during skin tumorigenesis. Concurrent expression of an activated H-ras gene and a mutant p53 gene was accomplished by crossing p53 Val135/wt mice with TGÁAC mice. Topical application to wild-type mice with benzo(a)pyrene (BaP) alone produced f26% skin tumor incidence, whereas BaP treatment of p53 wt/wt Hras TGÁAC/wt , p53 Val135/wt Hras wt/wt , and p53 Val135/wt Hras TGÁAC/wt mice produced a 75%, 77%, and 100% incidence of skin tumors, respectively. An average of 0.33 tumor per mouse was observed in wild-type (p53 wt/wt Hras wt/wt ) mice, whereas f1.54, 1.96, and 3.08 tumors per mouse were seen in BaP-treated p53 wt/wt Hras TGÁAC/wt , p53 Val135/wt Hras wt/wt , and p53 Val135/wt Hras TGÁAC/wt mice, respectively. The effects on total tumor volume were even more striking with 7-, 48-, and 588-fold increases in tumor volume compared with wild-type (p53 wt/wt Hras wt/wt ) in p53 wt/wt Hras TGÁAC/wt , p53 Val135/wt Hras wt/wt , and p53 Val135/wt Hras TGÁAC/wt mice, respectively. Histopathologically, all tumors from p53 wt/wt Hras wt/wt mice were either papillomas or well-differentiated squamous cell carcinomas, whereas the tumors in p53 wt/wt Hras TGÁAC/wt , p53 Val135/wt Hras wt/wt , and p53 Val135/wt Hras TGÁAC/wt mice were principally squamous cell carcinomas with varying degree of invasiveness. Particularly, tumors in p53 Val135/wt Hras TGÁAC/wt mice exhibited the most rapid growth and the extreme form of tumor invasion. Microarray analysis revealed that dominant-negative p53 (Val 135 ) and activated H-ras affected several cellular processes involved in tumorigenesis possibly through its effects on apoptosis, cell cycle arrest, and Ras-mitogen-activated protein kinase pathways. The present study provides the first in vivo evidence that a germ line p53 mutation and activated H-ras act synergistically to profoundly enhance tumor progression. (Mol Cancer Res 2005;3(10):563 -74)

CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma

“…When both CDKN2A and TP53 are mutated, the cascade of destabilization of the tumor cells progresses, and might indeed explain the worse survival of patients carrying both mutations. The worse survival in patients carrying TP53 and HRAS is in line with those of Zhang et al who showed a markedly increased number of tumors and tumor size in transgenic mice with TP53 and HRAS mutations [34]. The synergistic interaction and the resulting impairment of prognosis could be explained by the roles that both genes have in tumorigenesis.…”

Driven to Death: Inhibition of Farnesylation Increases Ras Activity and Promotes Growth Arrest and Cell Death

“…The relationship between decreased invasiveness and increased Ras activity when farnesylation is inhibited is also unclear and may be due to the functional inhibition of H-Ras. H-Ras has been reported to increase invasiveness of various carcinomas (42, 43). Raponi et al found expression of RASGRP1 , a guanine nucleotide exchange factor (GEF) that activates Ras, predicted sensitivity to tipifarnib treatment in AML (44).…”

Oncogenes do not Fully Override Cell-intrinsic Traits: Pronounced Impact of the Cellular Programme

“…Most importantly, inactivated TP53 and mutated c-Ha-RAS act synergistically in making cells vulnerable to chemically induced carcinogenesis in vitro and also in vivo [47, 48]. The ts p53 used in our work was shown to synergistically induce malignant transformation together with c-Ha-Ras in primary RECs [12].…”