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Thesis (Master's)

University of Iceland > Heilbrigðisvísindasvið > Meistaraprófsritgerðir - Heilbrigðisvísindasvið >

Please use this identifier to cite or link to this item: http://hdl.handle.net/1946/35793

  • Characterization of a mammalian specific function of the key autophagy gene ATG7.
  • Master's
  • Autophagy is an intracellular degradation process important for cellular homeostasis. Autophagy involves a formation of a double membraned autophagosome that engulfs material for degradation and subsequently fuses with the lysosome. The degradation occurs in the resulting autolysosome and the degraded material is transported to the cytosol or exocytosed. Cancer cells can utilize autophagy to sustain survival under stress conditions such as hypoxia and nutrient starvation within the tumor microenvironment. However, autophagy is also believed to act in a tumor suppressive manner as the process is important for maintaining the turnover of macromolecules and organelles within the cell.
    The essential autophagy gene ATG7 plays a major role in the initial stages of autophagosome formation. There are two isoforms of ATG7 expressed in human tissues, ATG7(1) and ATG7(2). The longer ATG7(1) isoform can promote autophagosome formation, however, the shorter ATG7(2) isoform is unable to carry out the autophagy role of the protein. The lab has previously identified a rare missense germline variant in the essential autophagy gene, ATG7, which associates with human hepatic cancer. This variant results in a coding change, D522E, in the ATG7 protein. Interestingly, the D522 residue is highly conserved among mammals and resides in a mammalian specific region of the ATG7 protein.
    The aim of this project was to characterize the function of this mammalian specific region. In order to do so we generated stable human hepatocellular carcinoma HuH7 and HepG2 cell lines expressing wild type ATG7(1), wild type ATG7(2) or either of the isoforms in which we have deleted the mammalian specific region (delMSR). We found that the deletion of the mammalian specific region in ATG7(2) resulted in decreased migration rate and a reduction in focal adhesions. As ATG7(2) is unable to carry out the characterized autophagy function of ATG7, these results imply that the mammalian specific region plays a role in a non-autophagy function of ATG7. Our findings provide a novel aspect on the function of ATG7. Considering the important role ATG7 plays in tumor biology, it will be important to take a potential non-autophagy function of the protein into account when developing therapeutic approaches involving the autophagy pathway.

  • Jun 2, 2020
  • http://hdl.handle.net/1946/35793

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