Claudin proteins and the regulation of epithelial proliferation and differentiation: A mutual correlation

Title: Claudin proteins and the regulation of epithelial proliferation and differentiation: A mutual correlation
Authors: Arabzadeh, Azadeh
Date: 2008
Abstract: One mode of cell-cell adhesion between epithelial and endothelial cells is mediated by tight junctions (TJs), complex structures which serve two major roles: (1) they constitute a barrier to the passage of ions and small molecules through the paracellular space and (2) they restrict the movement of lipids and proteins between the apical and basolateral compartments of the plasma membrane. It is now widely recognized that the Claudin (Cldn) family of tetraspan membrane proteins is crucial for TJ assembly and barrier function. Although originally proposed as structural components of TJs, recent evidence implicate the signaling function of Cldns. Notably, a bilateral correlation between Cldns and signal transduction pathways regulating cell proliferation/differentiation is emerging; on one hand Cldns can undergo changes in response to altered proliferation-differentiation, and on the other hand changes in Cldns can result in proliferation and/or differentiation perturbations. Along this line, studies from our laboratory have confirmed that such connection exists. Using the mouse epidermis as a model system, we first reported that overexpression of endogenous Cldn6 in this tissue perturbs both the balance of other Cldn isoforms as well as the normal process of epidermal differentiation. To elucidate the mechanism behind this effect, we looked towards the Cldn6 C-terminal tail; a region that may interact with yet-unidentified molecules involved in transducing signals of epidermal differentiation. Therefore, deletion of the tail domain was assumed to lead us to Cldn6 signaling function; indeed expression of tail-ablated Cldn6 not only disrupted epidermal differentiation but also increased cell proliferation. Loss of epidermal homeostasis was apparently due to the loss of Cldn homeostasis. We were next curious to know whether the correlation of Cldns to proliferation-differentiation is of a reciprocal nature. Therefore, two well-known models of tissue injury response and chemical carcinogenesis were used, in order to induce proliferation-differentiation aberrancy. Examining various Cldns in both models indicated that in response to perturbed proliferation-differentiation Cldns undergo changes, further raising a two-sided regulatory function between Cldns and intracellular signaling pathways.
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
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