EVIDENCE FOR ALTERATED WNT AND NOTCH SIGNALING IN A H-PRUNE TRANSGENIC MOUSE MODEL
De Vita, Gennaro (2011) EVIDENCE FOR ALTERATED WNT AND NOTCH SIGNALING IN A H-PRUNE TRANSGENIC MOUSE MODEL. [Tesi di dottorato] (Inedito)
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H-Prune protein stimulates cellular motility and metastasis process of breast cancer cells. The role of h-Prune in increased cell motility can be explained in part to h-Prune interaction with GSK-3β with which cooperatively works to regulate the disassembly of focal adhesions and promote cell migration. In the present study we use a transgenic mouse model to investigate the role of h-Prune in the epidermis. We uncover defects in stratification, differentiation and barrier formation which can be attributed to a failure in basal keratinocytes proliferation and migration of ML-h-Prune transgenic mice. We highlight a role of h-Prune in substaining Wnt/β-catenin pathway thus investigating the molecular mechanism underlying the observed phenotype. We notice that h-Prune overexpression lead to higher rate of GSK3-β phosphorylation resulting in its inactivation. To follow the Wnt pathway variation mediated by Prune in vivo, we generate a double transgenic mice model pVegfr2-luc/ML-h-Prune that shows an higher signal of bioluminescence driven by the pVegfr2 promoter, in agreement of the maximum peak of h-Prune expression. Thus these analyses in vivo show that h-Prune is able to enhance VEGF-α, through its substaining activation of the WNT signaling in the mouse skin. Because of the knowledge of Notch signaling involved into an altered differentiation pattern of keratynocytes, we observed in the ML-h-Prune transgenic skin an unbalanced differentiation phenotype, thus we decide to analyze the level of the Notch pathway activation in transgenic mice skin. We show here a substantial reduction of downstream effectors of these signaling in the h-Prune transgenic animals . The phenotype of our transgenic model is very close to an inflammatory phenotype, with unbalancing levels of both WNT and Notch pathways, thus postulating a correlation of h-Prune overespression and consequent inflammation into the mice skin. For these reasons we analyzed h-Prune together with β-catenin nuclearization in serial sections of human psoriatic skin, asserting an involvement of h-Prune in these pathology, a disease which retains both proinflammatory insult and higher WNT-activated proliferation phenotype. This model could be the base for future studies that will assess properties and functions of h-Prune in human disorders which are related to hyperproliferation and inflammation of the skin. This is an attempt to find molecular targets for future therapeutic applications in the treatment of inflammatory skin pathologies.
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