A study of skin homeostasis and skin tumorigenesis using transgenic mice

Kerr, Peter Joseph (2000) A study of skin homeostasis and skin tumorigenesis using transgenic mice. PhD thesis, University of Glasgow.

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Abstract

The ability to engineer mice which carry exogenous genes targeted for expression in specific tissues, or have an endogenous gene functionally switched off has allowed us to examine the role of particular proteins in an in vivo model. This technology, in combination with a well-characterised model of chemically-induced skin carcinogenesis in the mouse, has allowed us to start dissecting the changes that occur during a particular pathway of tumorigenesis. TGFbeta1 has been shown to act as an inhibitor of both normal cellular proliferation and tumour formation. However, it can also accelerate malignant conversion at later stages of carcinogenesis. Previously in this laboratory, mice were generated that overexpressed Tgfbetal in suprabasal layers of skin epidermis under the control of a K10 promoter. These transgenic mice showed an increased proliferation rate in the basal compartment of their epidermis compared to wild-type controls. In this study, it is shown that the change in proliferative index is not dependent on p53, a molecule central to growth control and apoptosis. The K10-Tgfbeta1 mice were crossed on to a Tgfbeta1-null background and the proliferative phenotype of the transgene was examined. An increased basal cell proliferative index was observed whether the background was Tgfbeta1-null or wild-type. TGFbeta1 has been shown to induce apoptosis and a line of transgenic mice overexpressing BCL-2 in the epidermis became available, providing an opportunity to investigate the role of an apoptotic pathway in the skin. These K10-BCL-2 mice were shown to express the transgene at both mRNA and protein levels in suprabasal cells of the epidermis. Normal skin homeostasis, however, was not disrupted by the exogenous BCL-2 and expression of other apoptotic markers was not altered in these mice. Purthermore, K10-5CL-2 mice responded to chemical insult by a skin tumour promoter in the same way as wild-type littermates. K10-Tgfbeta1 mice had demonstrated resistance to papilloma formation during chemical carcinogenesis and tumours on the transgenic mice had also shown a higher rate of malignant conversion in the same experiment. In this study, the effects of epidermally-targeted Tgfbeta1 during tumorigenesis were investigated further by crossing the K10-Tgfbeta1 mice to a tumour-developing K5-RAS transgenic line. Mice carrying both the K5-RAS and K10-Tgfbeta1 transgenes showed no difference in tumour formation compared to those harbouring just the K5-RAS transgene.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Rosemary Akhurst
Keywords: Oncology, Genetics
Date of Award: 2000
Depositing User: Enlighten Team
Unique ID: glathesis:2000-72204
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 24 May 2019 15:11
Last Modified: 24 May 2019 15:11
URI: http://theses.gla.ac.uk/id/eprint/72204

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