Primary cilia and the Hedgehog signaling pathway (Master thesis)

Κλημοπούλου, Μαρία

The Hedgehog signaling pathway is a major regulator of the developmental processes of multicellular organisms. Aside of its role in cellular differentiation and in organ formation during embryogenesis, it is also important in the regeneration and repair of the tissues. Aberrant activation of this pathway has been linked with a variety of human cancers. Several studies have shown that the major components of the Hedgehog pathway undergo reversible phosphorylation and dephosphorylation by protein kinases and phosphatases which are importnant regulators for fine-tuning of this pathway. Among these enzymes, protein phosphatase 2A (PP2A) is the best studied phosphatase in the Hedgehog signaling pathway and it has been shown to act as a positive regulator of the pathway. The SET/I2PP2A is a multifunctional protein with a wide range of functions in different cellular compartments and it is an inhibitor of PP2A. Having such a variety of functions, the protein SET is considered as a pharmaceutical target for several cancers. The aim of this work was to investigate the effect of the inhibition of SET function on the Hedgehog signaling pathway and on the formation of primary cilia, a unique microenvironment where the signaling cascade takes place. For the inhibition of SET function, two different inhibitors were used, the drug FTY720 and the peptide COG112. Our results showed that the percentage of cilia within the cell population was decreased upon treatment of NIH3T3 cells with FTY720. In addition, under these conditions, the translocation of SET from the cytoplasm to the plasma membrane was more pronounced. On the contrary, inhibition of SET function by COG112 did not affect the subcellular localization of SET. Interestingly, treatment of NIH3T3 cells by FTY720 and COG112 led to a significant decrease of the protein and mRNA levels of the Gli1 transcriptional factor, a strong activator of the Hedgehog pathway, without affecting SET expression. Taken together, the results of this work suggest that the pharmacological inhibition of SET affects and the formation of primary cilia and the Hedgehog pathway. Future studies will investigate in more detail the involvement of the oncoprotein SET in the Hedgehog signaling cascade.
Alternative title / Subtitle: ο ρόλος των φαρμακολογικών αναστολέων της ογκοπρωτεΐνης SET/I2PP2A
the role of pharmacological inhibitors of the SET / I2PP2A oncoprotein
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Subject classification: Κύτταρα
Keywords: Κροσσοί,SET,I2PP2A,Hedgehog,Primary cilia
Appears in Collections:Διατριβές Μεταπτυχιακής Έρευνας (Masters)

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