v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: Effects of phorbol esters and retinoic acid

Journal Article · Sat Dec 01 04:00:00 EST 1990 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.87.23.9178· OSTI ID:5074281

Leder, A; Sinn, E ^[1]; Kuo, A; Leder, P ^[2]; Cardiff, R D ^[3]

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1. Harvard Medical School, Boston, MA (United States)
2. Harvard Medical School, Boston, MA (United States) Howard Hughes Medical Inst., Boston, MA (United States)
3. Univ. of California, Davis (United States)

Experimental carcinogenesis has led to a concept that defines two discrete stages in the development of skin tumors: (i) initiation, which is accomplished by using a mutagen that presumably activates a protooncogene, and (ii) promotion, which is a reversible process brought about most commonly by repeated application of phorbol esters. The authors created a trangenic mouse strain that carries the activated v-Ha-ras oncogene fused to the promoter of the mouse embryonic {alpha}-like, {zeta}-globin gene. Unexpectedly, these animals developed papillomas at areas of epidermal abrasion and, because abrasion can also serve as a tumor-promoting event in mutagen-treated mouse skin, we tested these mice for their ability to respond to phorbol ester application. Within 6 weeks virtually all treated carrier mice had developed multiple papillomas, some of which went on to develop squamous cell carcinomas and, more frequently, underlying sarcomas. They conclude that the oncogene preinitiates carrier mice, replacing the initiation/mutagenesis step and immediately sensitizing them to the action of tumor promoters. In addition, treatment of the mice with retinoic acid dramatically delays, reduces, and often completely inhibits the appearance of promoter-induced papillomas. This strain has use in screening tumor promoters and for assessing antitumor and antiproliferative agents.

• OSTI ID: 5074281
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (United States) Vol. 87:23; ISSN 0027-8424; ISSN PNASA
• Country of Publication: United States
• Language: English

Related Subjects

560300* -- Chemicals Metabolism & Toxicology
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
BIOLOGICAL EFFECTS
BODY
CARBOXYLIC ACID ESTERS
CARCINOGENESIS
CARCINOGENS
ELECTROPHORESIS
ESTERS
GENE REGULATION
GENES
HISTOLOGY
MAMMALS
MICE
MOLECULAR BIOLOGY
ONCOGENES
ORGANIC COMPOUNDS
ORGANS
PATHOGENESIS
PHORBOL ESTERS
RETINOIC ACID
RODENTS
SKIN
VERTEBRATES