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Biochemical characterization of the ...

Zhou, Wen.

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Biochemical characterization of the estrogen receptor alpha (ERalpha) coactivator E6-Ap, SKPp2 and FBXL6.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Biochemical characterization of the estrogen receptor alpha (ERalpha) coactivator E6-Ap, SKPp2 and FBXL6./
Author:	Zhou, Wen.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2014,
Description:	128 p.
Notes:	Source: Dissertation Abstracts International, Volume: 75-09(E), Section: B.
Contained By:	Dissertation Abstracts International75-09B(E).
Subject:	Medicine. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3623774
ISBN:	9781303963858

Biochemical characterization of the estrogen receptor alpha (ERalpha) coactivator E6-Ap, SKPp2 and FBXL6.
Zhou, Wen.

Biochemical characterization of the estrogen receptor alpha (ERalpha) coactivator E6-Ap, SKPp2 and FBXL6. - Ann Arbor : ProQuest Dissertations & Theses, 2014 - 128 p.

Source: Dissertation Abstracts International, Volume: 75-09(E), Section: B.

Thesis (Ph.D.)--University of Miami, 2014.

This item is not available from ProQuest Dissertations & Theses.

Many transcription factors undergo transcription-coupled proteolysis. While ligand binding activates ubiquitin-proteolysis of estrogen receptor alpha (ERalpha), mechanisms governing this and its relationship to transcriptional activation were unclear. In this thesis, I present the evidence indicating that different ubiquitin ligases, including E6-AP and SCFSKP2 regulate ER protein stability and transcriptional activity.

ISBN: 9781303963858Subjects--Topical Terms:

641104
Medicine.

Biochemical characterization of the estrogen receptor alpha (ERalpha) coactivator E6-Ap, SKPp2 and FBXL6.
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020 $a 9781303963858
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100 1 $a Zhou, Wen. $3 2122813
245 1 0 $a Biochemical characterization of the estrogen receptor alpha (ERalpha) coactivator E6-Ap, SKPp2 and FBXL6.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2014
300 $a 128 p.
500 $a Source: Dissertation Abstracts International, Volume: 75-09(E), Section: B.
500 $a Adviser: Joyce M. Slingerland.
502 $a Thesis (Ph.D.)--University of Miami, 2014.
506 $a This item is not available from ProQuest Dissertations & Theses.
520 $a Many transcription factors undergo transcription-coupled proteolysis. While ligand binding activates ubiquitin-proteolysis of estrogen receptor alpha (ERalpha), mechanisms governing this and its relationship to transcriptional activation were unclear. In this thesis, I present the evidence indicating that different ubiquitin ligases, including E6-AP and SCFSKP2 regulate ER protein stability and transcriptional activity.
520 $a Data from E6-AP project presented link crosstalk between the Src kinase and liganded ERalpha with ERalpha activation and its ubiquitylation. Liganded ERalpha rapidly activates and recruits Src which phosphorylates ERalpha at tyrosine 537 (Y537). This enhances ERalpha binding to the ubiquitin ligase/ERalpha coactivator, E6-AP, stimulating ERalpha ubiquitylation, target gene activation and ultimately ERalpha loss. ERalpha phosphorylation by Src promotes ERalpha ubiquitylation by E6-AP and proteasomal degradation in vitro. Src inhibition impairs estrogen-activated ERalpha:E6-AP binding, reducing ERalpha degradation. ERalpha-Y537F shows little estrogen stimulated degradation and activates native ERalpha target genes poorly. Src activation enhances ERalpha and E6-AP binding and their occupancy at ERalpha target gene promoters to enhance transcription. Thus, ERalpha-Y537 phosphorylation drives ERalpha:E6-AP binding to at least a subset of target promoters, linking transcriptional activation to ERalpha degradation and providing a novel mechanism to fine tune ERalpha action.
520 $a Data from SKP2 project support a model in which estrogen-activated CyclinE-CDK2 binds and phosphorylates ERalpha-S341, to prime ERalpha-SCFSKP2 binding via SKP2-L248QTLL252 in late G1. SKP2 activates ERalpha ubiquitylation and proteolysis. Putative late ERalpha targets were identified by expression profiling, SKP2 knockdown attenuated E2F-1 and BLM induction. SKP2 overexpression, but not coactivator motif mutant SKP2-L 248QTAA252, enhanced estrogen-induced E2F-1 and BLM expression. SKP2 knockdown impaired estrogen-stimulated ERalpha, SKP2, SRC3 and PolII recruitment to E2F-1 and BLM promoters. This work not only identifies these late-activated genes as bone fide ERalpha targets but describes a novel mechanism for their periodic activation. SKP2 serves as dual ERalpha E3 ligase/coactivator for late-activated target genes, revealing a novel mechanism whereby ERalpha:SCFSKP2 transactivation of E2F-1 feeds forward to drive G1-to-S.
520 $a Preliminary data from FBXL6 project suggested another F-box protein, FBXL6, as a putative ER coactivator. FBXL6 protein and mRNA levels are cell cycle regulated, rising in early G1 to peak in late G1 and S phases. FBXL6 co-precipitates with SCFFBXL6 ubiquitin ligase components: cellular SKP1, RBX1, CUL1 and ER. Estrogen stimulates FBXL6-ER binding and this is inhibited by tamoxifen treatment Effects of FBXL6 overexpression and knockdown on estrogen stimulated ER proteolysis are being evaluated. Ectopic FBXL6 expression increases ER transcriptional activity in reporter assay, supporting a role for FBXL6 as an ER coactivator. Since FBXL6 levels and its binding to ER increase in late G1, we postulate that estrogen stimulated ER targets, co-regulated by FBXL6 also rise late, 9-12 hours after estrogen stimulation. Our gene expression array analysis revealed a subset of putative "late" ER target genes including CENPQ, CHAF1B, CDC6, and RAD54B, whose expression increases by over two fold between 6 and 12 hours after estrogen stimulation. Estrogen stimulates ER and FBXL6 binding to the CDC6 promoter in ChIP assays and FBXL6 knockdown diminishes estrogen-stimulated CDC6 expression. Cdc6 plays a key role to initiate DNA replication and its induction by ER-FBXL6 may represent a critical gatekeeping role for ER on DNA replication. The influence of FBXL6 on late ER target gene selection and biological consequence of the target selection are under investigation. Completion of these studies will provide novel mechanistic insights into FBXL6-ER-mediated transcriptional regulation, which may critically regulate DNA replication and repair to affect genome plasticity.
520 $a Experimental work of this thesis has elucidated novel molecular mechanisms whereby E3 ubiquitin ligases play dual roles as ER coactivators. These studies link ER proteolysis and activation of ER target genes and may not only prove to be relevant to hormone regulation of breast cancer but also reveal mechanisms whereby low level receptor expression governs gene action in several normal target tissues.
590 $a School code: 0125.
650 4 $a Medicine. $3 641104
650 4 $a Endocrinology. $3 610914
690 $a 0564
690 $a 0409
710 2 $a University of Miami. $b Biochemistry and Molecular Biology (Medicine). $3 3279332
773 0 $t Dissertation Abstracts International $g 75-09B(E).
790 $a 0125
791 $a Ph.D.
792 $a 2014
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3623774