Hyperproliferation and Defects in Epithelial Polarity upon Conditional Ablation of α-Catenin in Skin

Abstract

When surface epithelium was conditionally targeted for ablation of alpha-catenin, hair follicle development was blocked and epidermal morphogenesis was dramatically affected, with defects in adherens junction formation, intercellular adhesion, and epithelial polarity. Differentiation occurred, but epidermis displayed hyperproliferation, suprabasal mitoses, and multinucleated cells. In vitro, alpha-catenin null keratinocytes were poorly contact inhibited and grew rapidly. These differences were not dependent upon intercellular adhesion and were in marked contrast to keratinocytes conditionally null for another essential intercellular adhesion protein, desmoplakin (DP). KO keratinocytes exhibited sustained activation of the Ras-MAPK cascade due to aberrations in growth factor responses. Thus, remarkably, features of precancerous lesions often attributed to defects in cell cycle regulatory genes can be generated by compromising the function of alpha-catenin.

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

“…CTNNA1 encodes the protein -E-catenin, which functions in a complex with -catenin where it binds the cytoplasmic domain of E-cadherin to the cytoskeleton [36,37]. -E-catenin inhibition has been shown to destabilize adherens junctions, weakening the interaction between cells [38]. Currently, three families have been described with CTNNA1 germline mutations [35,39].…”

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

“…Conditional knockout of a-catenin in mouse epidermis showed not only adhesion and migration defects in the skin, but marked increases in Ras/MAPK signaling, hyperproliferation, and a significant presence of multinucleated cells (Vasioukhin et al, 2001). Conditional deletion of a-catenin in the mouse central nervous system led to severe hyperproliferation and dysplasia in the brain at E13.5 that was attributed to decreased cellular apoptosis and an accelerated cell cycle (Vasioukhin et al, 2001;Lien et al, 2006). Re-introduction of a-catenin into HL-60 myeloid leukemic cells (which harbor a 5q31 deletion encompassing CTNNA1) suppressed cellular proliferation though enhancing apoptotic death (Liu et al, 2007).…”

Adherens Junction: Molecular Architecture and Regulation

“…When a-catenin is removed, AJ organization is disrupted, and the apical actin belt becomes segregated from the cadherincatenin complex (Watabe- Uchida et al 1998). If this occurs in neural epithelia in vivo, their architecture is seriously damaged (Vasioukhin et al 2001). Removal of neural a-catenin (aN-catenin) from synaptic AJs destabilizes synaptic contacts (Abe et al 2004).…”