Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas

Abstract

An important feature of the development of many human and animal tumours is the appearance of pre-malignant benign lesions, some of which undergo further changes during progression to malignancy. Many of the currently accepted concepts of multi-stage carcinogenesis have been developed using an experimental model based on the chemical induction of tumours in mouse skin. In this system, many of the premalignant papillomas which arise are promoter-dependent, and appear to regress if promoter treatment is interrupted, whereas others progress to form autonomous benign lesions and, in some cases, malignant carcinomas. Although the number and nature of the events leading to malignancy are not known, DNA transfection experiments have led to the identification of several genes which may be qualitatively altered in tumour cells (see ref. 6 for review). We have previously shown that DNA from transplantable mouse skin carcinomas induced by chemical carcinogens has the ability to transform NIH/3T3 cells, and that the gene responsible for the transformation is an activated form of the mouse cellular Harvey-ras gene (c-rasH). We have now investigated the stage of carcinogenesis at which the proto-oncogene acquires transforming activity. We demonstrate that primary papillomas induced by chemical carcinogens in two different mouse strains have an activated c-rasH gene. This constitutes the first report of a benign tumour which contains DNA with detectable transforming activity. In addition, steady-state levels of c-rasH gene transcripts are elevated in the papillomas as compared with normal epidermis.

Elevated expression of the human ras oncogene family in premalignant and malignant tumours of the colorectum

“…Moreover, recent transfection studies have revealed the presence of a distantly related N-ras oncogene (Hall et al, 1983 (Spandidos, 1983) the elevation observed here is not in itself sufficient to produce malignant change. Parallel studies in this laboratory, of carcinogen induced mouse skin papillomata, which have a similar potential for malignancy, have also demonstrated elevated Ha-ras oncogene expression and in addition, the DNA from these tumours has acquired transforming activity in transfection assays (Balmain et al, 1984). The cellular homologues of several retroviral oncogenes have been shown to exhibit tissuespecific patterns of transcriptional activity (Westin et al, 1982a,b, Gonda et al, 1982.…”

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

“…Our result indicates that in longterm TPA treated skin TGF-b signaling through the type II receptor is still possible. In the mouse skin carcinogenesis model over 90% of papillomas and carcinomas initiated by DMBA have a speci®c A?T transversion in the codon 61 of the Harvey-ras gene (Balmain et al, 1984;. This mutation is su cient to initiate skin in vivo, but secondary events are necessary to induce the development of tumors Bailleul et al, 1990).…”

Expression of a binding protein for FGF is associated with epithelial development and skin carcinogenesis

“…DMBA treatment of skin causes mutations at codon 61 of the ras gene leading to rasactivation (Balmain et al, 1984;Hennings et al, 1988) and FGF-BP expression is increased in DMBA/TPA induced papillomas and in cell lines MK ras , SP1 and 308 that carry an activated ras gene. In addition, FGF-BP mRNA levels are upregulated in mouse skin after application of the PKC-activator TPA alone.…”

“…It has been shown that skin tumor initiation with DMBA causes an activating ras-mutation in codon 61 (Balmain et al, 1984). To test the hypothesis that ras activation plays a role for FGF-BP overexpression, we expressed activated ras in primary keratinocytes (MK ras ).…”