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postgraduate thesis: p70 S6 kinase regulation of Mdm2 and p53 in ovarian cancer cells during stress conditions

Titlep70 S6 kinase regulation of Mdm2 and p53 in ovarian cancer cells during stress conditions
Authors
Advisors
Advisor(s):Wong, AST
Issue Date2011
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Yam, H. B. [任憲章]. (2011). p70 S6 kinase regulation of Mdm2 and p53 in ovarian cancer cells during stress conditions. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4775310
AbstractOvarian cancer is a leading cause of death among of gynecological cancers. Current therapies are ineffective with a poor 5-year survival of only ~25%. p70 S6 kinase (p70 S6K) is a downstream target of the phosphatidylinositol 3-kinase pathway and is frequently activated in human ovarian cancer. However, the molecular targets and signaling pathways by which p70 S6K may affect tumor development and progression are poorly understood. Interestingly, in the laboratory, Mdm2, an important negative regulator of the p53 tumor suppressor, was identified in a yeast two hybrid screening of potential interacting partners for p70 S6K. In this study, I aimed to investigate the specific interaction of p70 S6K and Mdm2 and determine how this may contribute to ovarian tumorigenesis. Using a co-immunoprecipitation assay, the in vivo interaction of p70 S6K and Mdm2 in human ovarian cancer cells was confirmed. Upon UV-induced genotoxic stress, p70 S6K activation was associated with Mdm2 phosphorylation on S166 and subsequent p53 accumulation. This could be reversed by the use of rapamycin and p70 S6K siRNA to inhibit its kinase activity and expression respectively, confirming that the effect was p70 S6K specific. Conversely, ectopic expression of wildtype p70 S6K or a constitutively active mutant of p70 S6K, D3E-E389 (D3E) was sufficient to induce phosphorylation of Mdm2. Moreover, the p70 S6K mediated activation of Mdm2 was independent of p53 mutations. Similar results were observed upon other stress challenges such as hypoxia using hypoxia mimicking agent desferrioxamine (DFX). These findings identify Mdm2 as a new target of p70 S6K and reveal that p70 S6K intervenes the Mdm2-p53 regulatory loop in ovarian cancer, which may provide a survival advantage to cancer cells under stress conditions.
DegreeMaster of Philosophy
SubjectOvaries - Cancer - Genetic aspects.
p53 antioncogene.
p53 protein.
Protein kinases.
Dept/ProgramBiological Sciences

 

DC FieldValueLanguage
dc.contributor.advisorWong, AST-
dc.contributor.authorYam, Hin-cheung, Bill.-
dc.contributor.author任憲章.-
dc.date.issued2011-
dc.identifier.citationYam, H. B. [任憲章]. (2011). p70 S6 kinase regulation of Mdm2 and p53 in ovarian cancer cells during stress conditions. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4775310-
dc.description.abstractOvarian cancer is a leading cause of death among of gynecological cancers. Current therapies are ineffective with a poor 5-year survival of only ~25%. p70 S6 kinase (p70 S6K) is a downstream target of the phosphatidylinositol 3-kinase pathway and is frequently activated in human ovarian cancer. However, the molecular targets and signaling pathways by which p70 S6K may affect tumor development and progression are poorly understood. Interestingly, in the laboratory, Mdm2, an important negative regulator of the p53 tumor suppressor, was identified in a yeast two hybrid screening of potential interacting partners for p70 S6K. In this study, I aimed to investigate the specific interaction of p70 S6K and Mdm2 and determine how this may contribute to ovarian tumorigenesis. Using a co-immunoprecipitation assay, the in vivo interaction of p70 S6K and Mdm2 in human ovarian cancer cells was confirmed. Upon UV-induced genotoxic stress, p70 S6K activation was associated with Mdm2 phosphorylation on S166 and subsequent p53 accumulation. This could be reversed by the use of rapamycin and p70 S6K siRNA to inhibit its kinase activity and expression respectively, confirming that the effect was p70 S6K specific. Conversely, ectopic expression of wildtype p70 S6K or a constitutively active mutant of p70 S6K, D3E-E389 (D3E) was sufficient to induce phosphorylation of Mdm2. Moreover, the p70 S6K mediated activation of Mdm2 was independent of p53 mutations. Similar results were observed upon other stress challenges such as hypoxia using hypoxia mimicking agent desferrioxamine (DFX). These findings identify Mdm2 as a new target of p70 S6K and reveal that p70 S6K intervenes the Mdm2-p53 regulatory loop in ovarian cancer, which may provide a survival advantage to cancer cells under stress conditions.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.source.urihttp://hub.hku.hk/bib/B47753109-
dc.subject.lcshOvaries - Cancer - Genetic aspects.-
dc.subject.lcshp53 antioncogene.-
dc.subject.lcshp53 protein.-
dc.subject.lcshProtein kinases.-
dc.titlep70 S6 kinase regulation of Mdm2 and p53 in ovarian cancer cells during stress conditions-
dc.typePG_Thesis-
dc.identifier.hkulb4775310-
dc.description.thesisnameMaster of Philosophy-
dc.description.thesislevelMaster-
dc.description.thesisdisciplineBiological Sciences-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b4775310-
dc.date.hkucongregation2012-

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