Apoptosis is the mechanism by which complex multicellular organisms induce the programmed death of damaged cells, thus maintaining tissue homeostasis. One of the main hallmarks of cancer, apoptosis is tightly regulated by pro- and anti-apoptotic factors whose equilibrium will decide of the fate of the cell. Among these factors, the cellular inhibitor of apoptosis cIAP1 is a key regulator of nuclear factor-κB dependent signaling and of caspase-8 mediated apoptosis. cIAP1 expression is controlled primarily at the translational level through an internal ribosome entry site (IRES) that facilitates the recruitment of the ribosome to the translation initiation start independently of the 5’ cap. We have previously identified four putative IRES trans-acting factors (ITAFs) that bind specifically to the cIAP1 IRES, namely NF45, NF90, IGF2BP1 and RH1. My research project characterised NF45 as an ITAF that positively regulates the IRES-mediated translation of cIAP1 and of the Xlinked inhibitor of apoptosis, XIAP. This regulation is important for maintaining Survivin and Cyclin E protein levels and insuring proper cell division. Furthermore, I showed that IGF2BP1 is another ITAF that is overexpressed in rhabdomyosarcoma cancer (RMS) and positively regulates cIAP1 translation, thus leading to apoptotic resistance in these cells. Importantly, the use of Smac mimetics, chemical compounds that cause cIAP1 proteasomal degradation, induces TNFα-mediated apoptosis of RMS cells and leads to growth inhibition of RMS xenograft tumors as well as significantly improved survival. Finally, I show that certain modulators of innate immunity synergize with Smac mimetics to improve the killing of RMS cancer cells. Hence, cIAP1 translation regulation by NF45 and IGF2BP1 is highly important for maintaining proper functioning of the cell and dysregulation of these ITAFs can lead to carcinogenesis.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/32007 |
| Date | January 2015 |
| Creators | Faye, Mame Daro |
| Contributors | Holcik, Martin |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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