V-HA-RAS EXPRESSION, PROLIFERATION AND SKIN TUMORIGENESIS IN RAS TRANSGENIC MICE

Project: Research project

Description

Activation of the ras proto-oncogene has been found in multiple human
malignancies and is believed important in many tumorigenesis pathways. We
are using a transgenic mouse model which has a structural v-Ha-ras
transgene fused to a fetal zeta-globin promoter to study the events of
tumorigenesis associated with ras activation. These TG.AC strain
transgenic mice rapidly develop large numbers of epidermal papillomas
following TPA treatment, some of which progress to malignancy.
Histologically, the skin of the TG.AC mice is undistinguishable from that
of noncarrier FVB mice and responds with a similar down-regulation of
protein kinase C and hyperplasia following tetradecanoylphorbol-13-acetate
(TPA) treatment, except for the focal appearance of papillomas on TG.AC
skin. Using the techniques of Western blotting and in situ hybridization
histochemistry we have localized and quantitated transgenic ras mRNA and
protein product expression in epidermal papillomas and are in the process
of examining transgene expression in malignancies of the skin and other
tissues. Both Western blotting and in situ hybridization histochemistry
have demonstrated that the transgene message and protein product are
expressed in epidermal papillomas but not in normal or TPA-treated skin.
Using in situ hybridization histochemistry experiments the transgene
message was further localized to the basal epidermoid cells of the
papillomas. Immunohistochemical analysis for PCNA (proliferating cell
nuclear antigen) which is a marker for dividing cells localizes
proliferating cells of the papilloma to this same basal epidermoid cell
population. Thus, using in situ hybridization histochemistry for the
transgene message together with immunohistochemical analysis of dividing
cells we have shown an association of transgenic ras expression and
proliferation in the papillomas. Other experiments with papilloma
precursors have suggested that the papillomas develop focally from
keratinocytes associated with the hair follicle. Future experiments will
examine the role of the hair follicle in papilloma formation and pursue the
association of activated ras expression and proliferation.
StatusNot started

Funding

  • National Institutes of Health
  • National Institutes of Health

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Papilloma
Hair Follicle
Skin
Transgenic Mice
Carcinogenesis
Tetradecanoylphorbol Acetate
Neoplasms
Transgenes
In Situ Hybridization
Western Blotting
zeta-Globins
Epidermis
Hyperplasia
Odontogenic Tumors
ras Genes
Proto-Oncogenes
ras Proteins
Proliferating Cell Nuclear Antigen
Phosphotransferases
Down-Regulation