Kröger, Cornelia: Contributions of keratins to epithelial cell architecture and signaling. - Bonn, 2011. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc:
author = {{Cornelia Kröger}},
title = {Contributions of keratins to epithelial cell architecture and signaling},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2011,
month = jul,

note = {Keratin intermediate filament proteins form the major cytoskeleton in all epithelia. Increasing evidence suggests that keratins act as cytoskeletal scaffolds which locally regulate cell growth and survival. Many of these functions, however, are not understood in full, owing to keratin redundancy. Previous gene function studies have been impeded by gain of toxic function phenotypes. Therefore, transgenic mice lacking the entire keratin multiprotein family were analyzed and a corresponding keratinocyte cell line was generated.
The deletion of keratins resulted in prenatal death at E9.5 due to severe growth retardation. Within the scope of this thesis it was demonstrated that this was in part caused by repressed protein biosynthesis, due to mislocalized GLUTs mediated by the mTOR pathway. The analysis of extraembryonic tissue further revealed an influence of keratins on the adhesion between endodermal and mesodermal cell layers. As a consequence, keratin depleted embryos suffered from reduced yolk sac haematopoiesis and vasculogenesis, due to altered hormone and growth factor gradients. Similar effects were reported for mislocalized trophoblast giant cells in the absence of keratins which altered signaling and hormone secretion leading to increased vascularization of the maternal decidua. Hyperoxia in the decidua entailed defective Hif1α and VEGF signaling, resulting in impaired placental vasculogenesis and concomitant impairment of maternal and embryonic gas and nutrient exchange.
To overcome the limitation of an in vivo model in determining functions at the molecular level, a cell culture model was generated, the CK minus keratinocytes. First data indicated drastic changes in morphology of the ER and the Golgi complex, possibly ER stress, a hypothesis emerging form the acquired in vivo data of decreased glucose levels and increased hypoxia. Furthermore, similar to the mouse model desmosomes were altered, as demonstrated by DP and plectin relocalization and a misorganization of the actin cytoskeleton was observed. This suggests that the amount of keratin and eventually specific isotypes regulate formation and turnover of other multiprotein complexes, as cell junctions and other cytoskeletal systems, influencing cell attachment and migration in the epithelial tissue environment.
Translational control, restructuring of the tissue environment and cell migration are implications for stem cell turnover during development and tissue repair, as well as tumorigenesis. This thesis provides for the first time the tools, the CK minus cells, to examine the influences of keratin free or keratin isotype specific cells on tumor development and tissue regeneration by reinjection. Furthermore, with this easily accessible cell culture system, isotype-specific functions can be examined by re-expression of individual keratin pairs. This will help to understand the function of keratins in vivo including their associated diseases and will have implications for therapy approaches.},

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