Jayden
Cyrus
Right Open Reading Frame Kinase (RIOK2) is critical in ribosome assembly, which is needed for proliferating cancer cells. Targeting RIOK2 is shown to decrease tumor growth, likely due to impairment of ribosome biogenesis. Recently, our group discovered that RIOK2 has novel DNA binding activity, but there are still unknowns such as the cofactors it binds. A published high-throughput mass spectroscopy study suggests that RIOK2 interacts with RELA, a subunit of Nuclear Factor Kappa-light-chain-enhancer (NF-kB). NF- kB is a transcription factor that regulates genes essential for cancer cells. We hypothesize the RIOK2-NF-kB interaction supports disease progression. A nuclear fractionation experiment showed RIOK2 in the nucleus and cytoplasm. A co-immunoprecipitation assay of 22RV1 and PC3 cell lysates showed that NF-kB was bound to RIOK2 when not part of a ribosome complex. A drug combination assay indicated an additive ePect on proliferation when co-targeting both proteins. The results of preliminary studies validated the presence of an NF-kB -RIOK2 interaction in prostate cancer cells. Next, we will conduct a nuclear- fractionation assay targeting RIOK2 or NF-kB to understand where the interaction occurs and its regulation. Conversely, we will use NF-kB activating ligands to determine how activation of NF-kB aPects RIOK2-NF-kB binding. An understanding of this interaction is important to understand basic cancer cell biology and for potential translational interventions. Exploring the role of Draper in the glial induction of neuronal toxicity
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Authors:
Jayden Cyrus
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The spastin gene encodes a microtubule severing protein, and when mutated in humans leads to Autosomal Dominant Hereditary Spastic Paraplegia (AD-HSP), a neurodegenerative disease that impairs motor function in the legs. In Drosophila, spastin null larval neuromuscular junctions (NMJ) are characterized by a high synaptic bouton count with a "bunched" phenotype. In addition to neuronal proteins, glial proteins are also known to regulate synapses. One such protein is Pak3, a kinase that regulates actin polymerization and filopodial projections. Studies have shown that when Pak3 is deleted in spastin null Drosophila, neuronal structure and function are restored. While it is known that Pak3 deletion rescues the neurons by acting in subperineurial glia (SPG), the exact mechanism remains unclear. We hypothesize that Draper, an engulfment receptor in glia, may participate in this mechanism. Preliminary results indicate that, like Pak3 deletion, deleting draper and spastin rescues the spastin null phenotype, further demonstrating a requirement for glia in the pathology caused by loss of spastin. Additionally, although it is known that Draper functions in glia, the specific subtype of glia - wrapping, perineurial, or SPG - remains unknown. Therefore, my aim was to identify the specific subtype of glia in which Draper acts to cause the neuronal defects seen when spastin is lost. To do this, I knocked down Draper in a glial-specific manner using the UAS-GAL4 system to express draper-RNAi in a spastin null background. My results indicate that Draper works in perineurial and wrapping glia, but not SPG. Interestingly, this implies that while Pak3 works in SPG, Draper acts in other glia, implicating four diPerent cell types in this interaction: neurons, wrapping glia, perineurial glia, and SPG. Understanding the specific cell type(s) in which Draper acts will provide the first step in understanding how these proteins regulate neuronal structure and neuronal health, better our comprehension of how glia communicate with neurons and other glia, and shed light on the glial induction of neuronal toxicity.
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Duke University / 2024
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Co-authors:
Jayden Cyrus