Indefinite. Restriction lift date: 10000-01-01
Investigating the invasive and cytoprotective properties of the heme binding protein HRG-1 in cancer cells
| dc.check.date | 10000-01-01 | |
| dc.check.embargoformat | Both hard copy thesis and e-thesis | en |
| dc.check.entireThesis | Entire Thesis Restricted | |
| dc.check.info | Indefinite | en |
| dc.check.opt-out | Yes | en |
| dc.check.reason | This thesis is due for publication or the author is actively seeking to publish this material | en |
| dc.contributor.advisor | O'Connor, Rosemary | en |
| dc.contributor.author | Fogarty, Fionola | |
| dc.contributor.funder | Health Research Board | en |
| dc.contributor.funder | Science Foundation Ireland | en |
| dc.date.accessioned | 2015-06-03T09:27:39Z | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014 | |
| dc.description.abstract | This thesis investigates the mechanisms by which HRG-1 contributes to the invasive and cytoprotective signalling pathways in cancer cells through its effects on VATPase activity and heme transport. Plasma membrane-localised V-ATPase activity correlates with enhanced metastatic potential in cancer cells, which is attributed to extrusion of protons into the extracellular space and activation of pH-sensitive, extracellular matrix degrading-proteases. We found that HRG-1 is co-expressed with the V-ATPase at the plasma membrane of certain aggressive cancer cell types. Modulation of HRG-1 expression altered both the localisation and activity of the VATPase. We also found that HRG-1 enhances trafficking of essential transporters such as the glucose transporter (GLUT-1) in cancer cells, and increases glucose uptake, which is required for cancer cell growth, metabolism and V-ATPase assembly. Heme is potentially cytotoxic, owing to its iron moiety, and therefore the trafficking of heme is tightly controlled in cells. We hypothesised that HRG-1 is required for the transport of heme to intracellular compartments. Importantly, we found that HRG-1 interacts with the heme oxygenases that are necessary for heme catabolism. HRG-1 is also required for trafficking of both heme-bound and nonheme-bound receptors and suppression of HRG-1 results in perturbed receptor trafficking to the lysosome. Suppression of HRG-1 in HeLa cells increases toxic heme accumulation, reactive oxygen species accumulation, and DNA damage resulting in caspasedependent cell death. Mutation of essential heme binding residues in HRG-1 results in decreased heme binding to HRG-1. Interestingly, cells expressing heme-binding HRG-1 mutants exhibit decreased internalisation of the transferrin receptor compared to cells expressing wildtype HRG-1. These findings suggest that HRG- 1/heme trafficking contributes to a hitherto unappreciated aspect of receptormediated endocytosis. Overall, the findings of this thesis show that HRG-1-mediated regulation of intracellular and extracellular pH through V-ATPase activity is essential for a functioning endocytic pathway. This is critical for cells to acquire nutrients such as folate, iron and glucose and to mediate signalling in response to growth factor activation. Thus, HRG-1 facilitates enhanced metabolic activity of cancer cells to enable tumour growth and metastasis. | en |
| dc.description.sponsorship | Health Research Board (PhD Scholars Programme in Cancer Biology (FF)); Science Foundation Ireland (PI Award: 06/INI/B107) | en |
| dc.description.status | Not peer reviewed | en |
| dc.description.version | Accepted Version | |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.citation | Fogarty, F. 2014. Investigating the invasive and cytoprotective properties of the heme binding protein HRG-1 in cancer cells. PhD Thesis, University College Cork. | en |
| dc.identifier.uri | https://hdl.handle.net/10468/1839 | |
| dc.language.iso | en | en |
| dc.publisher | University College Cork | en |
| dc.rights | © 2014, Finola Fogarty. | en |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | en |
| dc.subject | Heme | en |
| dc.thesis.opt-out | true | |
| dc.title | Investigating the invasive and cytoprotective properties of the heme binding protein HRG-1 in cancer cells | en |
| dc.type | Doctoral thesis | en |
| dc.type.qualificationlevel | Doctoral | en |
| dc.type.qualificationname | PhD Scholars Programme in Cancer Biology | en |
