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The Regulation of Nuclear Receptor Coactivator SRC-3 Activity Through Membrane Receptor Mediated Signaling Pathways

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Annual rept. 23 Apr 2005-22 Apr 2006

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SRC-3AIB1 is a steroid receptor coactivator with potent growth promoting activity. It is overexpressed in a number of cancers and has been shown to have oncogenic potential. An important mechanism for the regulation of SRC-3 coactivator activity is its site-specific phosphorylation status which is controlled by extracellular signals that stimulate specific protein kinase signaling pathways. It is well known that protein kinases such as aPKC are frequently overexpressed in cancers and that phosphorylation of SRC-3 can contribute to its oncogenic potential. However it is unclear whether protein kinases can directly regulate SRC-3AIB1 cellular protein levels. In the present study we showed that a typical protein kinase C aPKC phosphorylates and stabilizes SRC-3 increased intracellular levels of the coactivator result in significant enhancement of steroid receptor transcription activity. The aPKC stabilization effect requires the presence of estrogen receptor. Using a variety of estrogen receptor mutants we found that this stabilization occurs primarily in the nucleus and is dependent on a direct interaction between SRC-3 and estrogen receptor. Furthermore we showed that aPKC-phosphorylated SRC-3 becomes resistant to degradation by the 26s proteasome in a cell-free degradation assay using all purified components of SRC-3 ER and 26s proteasome. Taken together our results suggest that in addition to its role in activation of this important SRC-3 growth coactivator phosphorylation also plays a role in regulating SRC-3 stability and turnover. Thus aberrant levels of select protein kinases such as aPKC in cancer cells might contribute to the high levels of SRC-3 seen in endocrine cancers.

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  • Medicine and Medical Research
  • Organic Chemistry

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