Elucidating the role of transglutaminase 2 in cellular response to hypoxic stress
Başlık çevirisi mevcut değil.
- Tez No: 403009
- Danışmanlar: Belirtilmemiş.
- Tez Türü: Doktora
- Konular: Fizyoloji, Physiology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2010
- Dil: İngilizce
- Üniversite: University of Rochester
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 194
Özet
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Özet (Çeviri)
Transglutaminase 2 (TG2) is a multifunctional enzyme that has guanine nucleotide binding and GTP hydrolyzing activity in addition to its transamidating function. Studies show that TG2 is a player in mediating cell death processes. However, there is far from a consensus about the role of this enzyme in cell death processes as it appears to be dependent upon the cell type, stimuli, subcellular localization and conformational state of the enzyme. Recently, we have shown that nuclear TG2 is protective in cellular and animal models of ischemic cell death. The purpose of this study was to dissect the role of TG2 in the cell death processes, with a focus on ischemic cell death. In the the first part of this study we created and characterized 4 distinct point mutants of TG2, each of which differs from the wild type by its conformation or by lacking an important function. We also prepared these mutants as nuclear targeted proteins by adding a nuclear localization signal (NLS). By overexpressing mutant or wild type forms of TG2 in HEK 293 cells, we investigated the modulatory role of the protein in the cell death process in response to three stressors: thapsigargin, hyperosmotic stress and oxygen/glucose deprivation (OGD). All of the TG2 constructs, except the R580A mutant (which cannot bind guanine nucleotides and is therefore more prone to exhibit transamidating activity), either did not significantly affect the cell death processes or were protective. However in the case of the R580A mutant cell death in response to high thapsigargin concentrations, was significantly increased. Intriguingly, nuclear localization of R580A-TG2 w sufficient to counteract the pro-death role of cytoplasmic R580A-TG2. In addition, nuclear localization of TG2 significantly facilitated its protective role against OGD. Our data support the hypothesis that the transamidation activity of TG2, which stays quiescent to a great extent except in extreme stress conditions, is necessary for its pro-death role. In addition, nuclear localization of TG2 generally plays a key role in its protective function against cell death processes, either counteracting the detrimental effect or strengthening the protective role of the protein. At the second part of this study, we have focused on the role of nuclear TG2 on OGD induced cell death. Since our initial studies were conducted with overexpression models, we first tested whether endogenous levels of TG2 have an effect on hypoxia responsive transcription and OGD-induced cell death. Depleting endogenous levels of TG2 increased the expression levels of hypoxia inducible factor (HIF) target genes and increased cell survival under OGD-induced stress. We, then used TG2 constructs with an added NLS or nuclear export signal (NES) to confirm that nuclear, not cytosolic, TG2 is responsible for the observed effect on hypoxic signaling and OGD induced cell death. We also provided evidence supporting the hypothesis that nuclear TG2 directly regulates hypoxia responsive transcription by showing that TG2 is recruited to the hypoxia response element (HRE) bearing portions of HIF target genes in hypoxia, but not in normoxia. Lastly, we examined whether the interaction between TG2 and the β subunit of HIFs, which was previously demonstrated by our group, is involved in TG2-dependent suppression of HIF signaling. To this end, we determined the interacting domains of TG2 and HIF1β and used this information to directly test if the interaction has functional outcomes in hypoxic signaling. Our preliminary results suggest that this interaction might contribute to the nuclear accumulation of TG2 in hypoxia, but is not required for the suppressive effect of TG2 on HIF activity. To sum up, our results illuminate the complexity of TG2's role in cell death/survival processes. However, the protective effect of transamidase inactive nuclear TG2 was a common occurrence in our models. We have studied the mechanism of this protection in one particular cell death model: OGD. The results of this study partially delineated the mechanism of the protection mediated by nuclear TG2. Our results suggest that nuclear TG2 directly regulates transcription independent of its transamidating activity. Overall, our studies have made a significant contribution to the understanding of the physiological roles of nuclear TG2, which remains a highly understudied field.
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