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The catalytic subunit of the proteasome is engaged in the entire process of estrogen receptor-regulated transcription.

ABSTRACT: The ubiquitin-proteasome system plays an important role in a variety of cellular functions by means of its proteolytic activity. Interestingly, recent studies have indicated that the proteasome components are also integral parts of transcription complexes. In genome-wide screening for steroid receptor coactivator (SRC)-interacting proteins using yeast two-hybrid system, we found that the 20S proteasome beta subunit LMP2 (Low Molecular mass Polypeptide 2) interacts directly with the SRC coactivators. We showed that LMP2 is required for estrogen receptor (ER)-mediated gene transcription and for estrogen-stimulated cell cycle progression. We found that LMP2-associated proteasome is recruited to the entire sequence of ER target genes, implicating a role for the proteasome in both transcription initiation and elongation. We demonstrated that the recruitment of LMP2 by SRC coactivators is necessary for cyclic association of ER-regulated transcription complexes on ER targets. These results revealed a mechanism by which the proteasome machinery is recruited in ER-mediated gene transcription. Our experiments also provided evidence implicating SRC coactivators in gene transcription elongation.

SUBMITTER: Zhang H

PROVIDER: S-EPMC1570434 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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The catalytic subunit of the proteasome is engaged in the entire process of estrogen receptor-regulated transcription.

Zhang Hua H Sun Luyang L Liang Jing J Yu Wenhua W Zhang Ying Y Wang Yan Y Chen Yupeng Y Li Ruifang R Sun Xiaojing X Shang Yongfeng Y

The EMBO journal 20060907 18

The ubiquitin-proteasome system plays an important role in a variety of cellular functions by means of its proteolytic activity. Interestingly, recent studies have indicated that the proteasome components are also integral parts of transcription complexes. In genome-wide screening for steroid receptor coactivator (SRC)-interacting proteins using yeast two-hybrid system, we found that the 20S proteasome beta subunit LMP2 (Low Molecular mass Polypeptide 2) interacts directly with the SRC coactivat ...[more]

PMID: 16957778

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Project description:Cellular levels of estrogen receptor-alpha (ERalpha) protein are regulated primarily by the ubiquitin-proteasome pathway. Dynamic interactions between ERalpha and the protein degradation machinery facilitate the down-regulation process by targeting receptor lysine residues for polyubiquitination. To date, the lysines that control receptor degradation have not been identified. Two receptor lysines, K302 and K303, located in the hinge-region of ERalpha, serve multiple regulatory functions, and we examined whether these might also regulate receptor polyubiquitination, turnover, and receptor-protein interactions. We used ERalpha-negative breast cancer C4-12 cells to generate cells stably expressing wild-type (wt)ERalpha or ERalpha with lysine-to-alanine substitutions at K302 and K303 (ERalpha-AA). In the unliganded state, ERalpha-AA displayed rapid polyubiquitination and enhanced basal turnover, as compared with wtERalpha, due to its elevated association with the ubiquitin ligase carboxy terminus of Hsc70-interacting protein (CHIP) and the proteasome-associated cochaperone Bag1. Treatment of C4-12 cells with either 17beta-estradiol (E2) or the pure antiestrogen ICI 182,780 (ICI) induced rapid degradation of wtERalpha via the ubiquitin-proteasome pathway; however, in the presence of these ligands, ERalpha-AA was less efficiently degraded. Furthermore, ERalpha-AA was resistant to ICI-induced polyubiquitination, suggesting that these lysines are polyubiquitinated in response to the antiestrogen and demonstrate a novel role for these two lysines in the mechanism of action of ICI-induced receptor down-regulation. The reduced stability of ERalpha-AA in the unliganded state and the increased stability of ERalpha-AA in the liganded state were concordant with reporter gene assays demonstrating that ERalpha-AA has lower basal activity but higher E2 inducibility than wtERalpha. These data provide the first evidence that K302/303 protect ERalpha from basal degradation and are necessary for efficient E2- and ICI-induced turnover in breast cancer cells.

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The catalytic subunit of the proteasome is engaged in the entire process of estrogen receptor-regulated transcription.

Publications

The catalytic subunit of the proteasome is engaged in the entire process of estrogen receptor-regulated transcription.

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