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dc.contributor.advisor Nephew, Kenneth P en
dc.contributor.author Berry, Nicholas en
dc.date.accessioned 2010-06-04T14:49:52Z
dc.date.available 2011-05-14T11:14:16Z
dc.date.issued 2010-06-04T14:49:52Z
dc.date.submitted 2008 en
dc.identifier.uri http://hdl.handle.net/2022/8083
dc.description Thesis (PhD) - Indiana University, Cellular and Integrative Physiology, 2008 en
dc.description.abstract Breast cancer is the most common cancer among women, and the majority (~70%) express estrogen receptor-alpha (ERα), thereby exhibiting estrogen-dependent growth. Antiestrogen therapies block ERα-mediated cell growth, either by blocking ERα function or by triggering ERα degradation. ERα is recognized for degradation by the 26S proteasome through the addition of ubiquitin protein tags onto ERα lysine residues. However, the specific receptor lysines that are ubiquitinated have not been identified. Two receptor lysines, K302 and K303, located in the hinge-region of ERα, serve multiple regulatory functions, and we examined whether these residues might also regulate receptor ubiquitination or are targets themselves for ubiquitination. An ERα protein was generated that contained lysine-to-alanine substitutions at these two residues. Comparisons were made between the unmodified ERα (wtERα) and the mutant receptor ERα-K302A, K303A (ERα-AA). The effect of the proteasome inhibitor MG132, Hsp90 inhibitor geldanamycin (GA), and ER ligands 17β-estradiol (E2), tamoxifen (OHT), and the pure antiestrogen ICI 182,780 (ICI), were examined for their effect on receptor ubiquitination, degradation, and receptor activity. In the absence of ligand, ERα-AA displayed rapid ubiquitination and degradation due to elevated association with the ubiquitinylation enzyme CHIP and the proteasome-associated cochaperone Bag1. E2 or ICI induced rapid degradation of wtERα; however, ERα-AA was less efficiently degraded by these ligands. Furthermore, ERα-AA was also resistant to ICI-induced ubiquitination, suggesting that these lysines are ubiquitinated in response to the antiestrogen. ERα-AA activity was decreased in the unliganded state and elevated in response to E2, concordant with receptor stability in these two states. These data provide the first evidence that K302/303 protect ERα from basal degradation and are necessary for efficient E2 and ICI-induced turnover in breast cancer cells, revealing a previously unexplored mechanism for regulating ERα stability and activity. en
dc.language.iso EN en
dc.publisher [Bloomington, Ind.] : Indiana University en
dc.subject estrogen en
dc.subject estrogen receptor en
dc.subject breast cancer en
dc.subject ubiquitin en
dc.subject proteasome en
dc.subject antiestrogen en
dc.subject.classification Biology, Molecular en
dc.subject.classification Biology, Cell en
dc.subject.classification Health Sciences, Oncology en
dc.title Regulation of Estrogen Receptor alpha Ubiquitination and Proteasome-mediated Receptor Degradation en
dc.type Doctoral Dissertation en


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