Keratinocyte as a model system for transcriptional control of epithelial homeostasis and carcinogenic transformation

Keratinocytes are specialized epithelial cells making up most of the stratified squamous epithelia of the mammalian epidermis and oral mucosa. In these epithelial tissues, the keratinocytes are arranged such that the proliferative, least differentiated cells are located in the innermost basal layer while the suprabasal cells are in a progressive state of differentiation towards the surface. The proliferation of keratinocytes is in a state of dynamic balance with the differentiation under physiological conditions. This equilibrium is maintained by a number of endogenous factors. Transcription factors are an integral part of the regulatory mechanisms that function in maintaining this homeostasis. In this thesis, I have examined the keratinocyte specific functions of two widely expressed transcription factors namely Ets1 and AP2alpha by gain-of-function and loss-of-function studies respectively. Both these transcription factors are expressed predominantly in the basal keratinocytes of the epidermis and appear to have distinct roles in keratinocyte physiology. Over expression of Ets1 in the basal layer affects the keratinocyte homeostasis minimally, while its ectopic expression in the suprabasal layers leads to extensive dysplastic changes associated with a block in terminal differentiation and enhanced proliferation. This indicates that the predominant function of Ets1 in the epidermal keratinocytes is in the maintenance of an undifferentiated state. Basal expression of a dominant negative form of AP2alpha again affected the keratinocyte differentiation while enhancing the proliferation, suggesting that its functions could be counteractive to Ets1 in the epidermis.