Ovarian 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. / published_or_final_version / Biological Sciences / Master / Master of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/174490 |
| Date | January 2011 |
| Creators | Yam, Hin-cheung, Bill., 任憲章. |
| Contributors | Wong, AST |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47753109 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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