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Title: Investigating Mechanisms by which the Localization of Rac1b is regulated by Hypoxia
Authors: Thomson, Daniel S.
Advisors: Nelson, Celeste M.
Department: Molecular Biology
Class Year: 2016
Abstract: Rac1b, a highly active splice variant of the small GTPase Rac1, is implicated in the progression of many human cancers. When Rac1b localizes to the membrane, it interacts with downstream effectors which can lead to cancer progression. Hypoxia, or the deprivation of adequate oxygen, is a characteristic of many tumors. It was recently shown that Rac1b translocalizes to the nucleus under hypoxia. We sought to confirm this result, and better understand the mechanisms underlying the translocalization. First, we found that Rac1b shows increased nuclear localization in low oxygen, confirming previous findings. We predicted two specific proteins may be involved in Rac1b translocalization. SmgGDS, a guanine nucleotide exchange factor (GEF) was shown to be necessary for Rac1b translocation. Interestingly, we found that SmgGDS has reduced expression under hypoxia. We also hypothesized that HMG-CoA reductase (HMGCR) may be involved in Rac1b translocalization. HMGCR is a critical enzyme in the mevalonate pathway, which synthesizes the prenyl group used by Rac1b for membrane targeting. To test whether HMGCR is involved in Rac1b translocalization, we treated cells with an HMGCR inhibitor. Treated cells had higher nuclear localization of Rac1b. Most importantly, there was no difference in localization between differing oxygen levels of cells with sufficient inhibitor treatment. We also found reduced HMGCR expression under hypoxia. These mechanistic insights for Rac1b translocalization may have important implications for understanding cancer progression.
Extent: 55 pages
Type of Material: Princeton University Senior Theses
Language: en_US
Appears in Collections:Molecular Biology, 1954-2017

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