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dc.contributor.advisorJackson, Twila A.
dc.contributor.authorScully, Melanie
dc.contributor.committeememberReyland, Mary
dc.contributor.committeememberColgan, Sean P.
dc.contributor.committeememberGraham, Douglas
dc.contributor.committeememberHurt, Kenneth J.
dc.date.accessioned2007-01-03T06:56:42Z
dc.date.available2007-01-03T06:56:42Z
dc.date.submitted2014
dc.descriptionSummer
dc.descriptionIncludes bibliographical references.
dc.description.abstractHyperestrogenicity is a risk factor for endometrial cancer. 17β-estradiol (E2) is known to stimulate both genomic and nongenomic estrogen receptor-α (ERα) actions in a number of reproductive tissues. However, the contributions of transcription-independent ERα signaling to normal and malignant endometrium and other steroid responsive cells are not fully understood. Phosphatase and tensin homolog (PTEN) is a tumor suppressor that decreases cellular mitosis primarily through negative regulation of the phosphoinositide 3-kinase (PI3K)/AKT signaling axis. PTEN levels are elevated during the E2 dominated, mitotically active, proliferative phase of the menstrual cycle, indicating possible hormonal regulation of PTEN in the uterus. In order to determine if rapid E2 signaling regulates PTEN, I used ERα positive, PTEN positive, endometrial cells and breast cancer cells. I show that cytosolic E2/ERα signaling leads to increased phosphorylation of PTEN at key negative regulatory residues in endometrial cells and breast cancer cells. Importantly, E2 stimulation decreased PTEN lipid phosphatase activity and caused consequent increases in phosphorylation of AKT at active site residues. I further demonstrate that cytosolic ERα forms a complex with PTEN in an E2 dependent manner, and that ERα constitutively complexes with protein kinase2-α (CK2α), a kinase previously shown to phosphorylate the C-terminal tail of PTEN. These results provide mechanistic support for an E2-dependent, ERα cytosolic signaling complex that negatively regulates PTEN activity through carboxy terminal phosphorylation. Using an animal model, I show that sustained E2 signaling results in increased phospho-PTEN at negative regulatory residues, S380, T382, T383, total PTEN and phospho-AKT (S473). Further experimentation in breast cancer cells shows E2 stimulation activates NFĸB subunit, RelA, accumulation into the nucleus, and increased transcription of pro-inflammatory cytokine IL-8, a target of NFĸB. Taken together, I provide a novel mechanism in which transcription-independent E2/ERα signaling may promote a pro-tumorigenic environment in the endometrium and other steroid regulated cells.
dc.identifierScully_ucdenveramc_1639D_10166.pdf
dc.identifier.urihttp://hdl.handle.net/10968/632
dc.languageEnglish
dc.publisherUniversity of Colorado Anschutz Medical Campus. Strauss Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.subject.meshPTEN Phosphohydrolase
dc.subject.meshReceptors, Estrogen
dc.subject.meshEstrogens
dc.subject.meshEndometrial Neoplasms
dc.titleRapid estrogen signaling regulates PTEN: implications for cancer risk in steroid responsive tissues
dc.typeThesis
thesis.degree.disciplineMolecular Biology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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