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Please use this identifier to cite or link to this item: http://dspace.mediu.edu.my:8181/xmlui/handle/1957/6120
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dc.contributorMerrill, Gary F.-
dc.contributorSchimerlik, Michael I.-
dc.contributorFrei, Balz B.-
dc.contributorHagen, Tory M.-
dc.contributorZabriskie, Mark T.-
dc.date2007-07-19T13:39:57Z-
dc.date2007-07-19T13:39:57Z-
dc.date2007-06-14-
dc.date2007-07-19T13:39:57Z-
dc.date.accessioned2013-10-16T07:56:58Z-
dc.date.available2013-10-16T07:56:58Z-
dc.date.issued2013-10-16-
dc.identifierhttp://hdl.handle.net/1957/6120-
dc.identifier.urihttp://koha.mediu.edu.my:8181/xmlui/handle/1957/6120-
dc.descriptionGraduation date: 2008-
dc.descriptionAerobic organisms have evolved many sensory mechanisms that allow response to oxidants in the environment. One area of interest is the relationship between the activity of the tumor suppressor protein p53 and the redox state of thioredoxin. Human p53 activity is severely compromised in budding yeast lacking thioredoxin reductase. Evidence suggests p53 may similarly require an intact thioredoxin system in mammals. One explanation for thioredoxin reductase dependence is that p53 cysteines may form inhibitory oxidation products. To test this idea, each p53 cysteine was changed to serine, and the effect on p53 activity in wildtype and thioredoxin reductase-null yeast was determined. Basal activity of each allele was confirmed in p53-null H1299 cells. As expected, substitutions at zinccoordinating cysteines C176, C238 or C242 resulted in p53 inactivation. Unexpectedly, substitution at cysteine C275 also inactivated p53, which is the first evidence for a non-zinc-coordinating cysteine being essential for p53 function. Substitutions at six positions (C124, C135, C141, C182, C229 and C277) neither inactivated p53 nor relieved the requirement for thioredoxin reductase, either singly or in combination. The results suggest that p53 dependence on thioredoxin reductase either was an indirect effect or was due to oxidation of one or more of the four essential cysteines. Another area of interest is the role of peroxiredoxins in oxidant response and signaling. Eukaryotic 2-Cys peroxiredoxins are sensitive to substrate inactivation at moderate H2O2 concentrations. The sensitivity of eukaryotic peroxiredoxins may have evolved as a mechanism to facilitate H2O2 signaling. For example, inactivation of protein tyrosine phosphatases by H2O2 may be necessary for efficient signaling by receptor tyrosine kinases, and peroxiredoxin inactivation may be necessary to prolong episodes of PTP inactivation. To test this model, we measured the oxidation state of peroxiredoxins and the phosphorylation state of EGF receptor in EGF- and peroxidechallenged A431 cells. Peroxide treatment sufficient to half-maximally inactivate Prx2, 3 and 6 did not increase EGFR tyrosine phosphorylation. EGF treatment sufficient to stimulate EGFR tyrosine phosphorylation levels had no effect on the oxidation state of Prx2, 3 or 6. Thus, global oxidation of cytosolic Prx was neither sufficient nor necessary for efficient EGFR phosphorylation.-
dc.languageen_US-
dc.subjectp53-
dc.subjectthioredoxin-
dc.subjectredox-
dc.subjectreceptor tyrosine kinase-
dc.subjectfloodgate-
dc.subjectperoxide-
dc.subjectperoxiredoxin-
dc.subjectprotein tyrosine phosphatase-
dc.subjectEGF-
dc.subjectEGFR-
dc.subjectgrowth factor-
dc.subjectYap1-
dc.subjectoxidative regulation-
dc.titleControl of p53 tumor suppressor and peroxiredoxin activity through shifts in cellular redox balance-
dc.typeThesis-
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