Ryan, Katie Rose (2010)
Ph.D. thesis, University of Birmingham.
The human epidermis is a self-renewing stratified epithelial tissue that forms the outermost protective layer of the skin. The epidermis is comprised of a number of cell types, the most abundant of which are keratinocytes. Normal function of the epidermis requires that keratinocyte proliferation, differentiation, and apoptosis be precisely regulated and a failure to regulate these processes is a feature of many skin diseases. Although the precise mechanism by which epidermal homeostasis is regulated is still far from clear, much progress has been made in the characterisation of signaling pathways involved in normal epidermal function. A key group of signaling proteins that have been clearly implicated in epidermal function are the Rho family of small GTP-binding proteins. This thesis focuses on one member of the family, RhoE/Rnd3, and the analysis of the role it plays in the regulation of proliferation, differentiation, apoptosis and cell-cell adhesion in the epidermis. Use of RNA interference to specifically ‘knock-down’ expression of RhoE has led to the discovery of a novel role for RhoE in regulation of cell-cell adhesion and apoptosis. Loss of RhoE expression resulted in keratinocytes developing resistance to apoptosis mediated via either the intrinsic or extrinsic pathways. RhoE depletion was also associated with increased expression of desmosomal proteins and increased numbers of desmosomes. Resistance to apoptosis was shown to be a function of desmosome-mediated cell-cell adhesion and a component of demosomes – plakoglobin – was shown to play a key role in RhoE-mediated resistance to apoptosis.
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