17β-Estradiol-induced cell proliferation requires estrogen receptor (ER) α monoubiquitination

Rosa, Piergiorgio La; Pesiri, Valeria; Marino, Maria; Acconcia, Filippo

doi:10.1016/j.cellsig.2011.02.006

Cited by 32 publications

(43 citation statements)

References 25 publications

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“…4A) without affecting E2 binding affinity (Table 1). This effect was still evident when the E2-induced ERa LAAG mutant transcriptional activity was tested in the presence of a reporter construct containing the ERE sequence in the context of the protein complement 3 (pC3) natural promoter (La Rosa et al, 2011b) (Fig. 4B).…”

Section: Role Of Era-ubs In E2-induced Era Gene Transcriptionmentioning

confidence: 95%

“…HeLa and HEK293 cells were grown as previously described (La Rosa et al, 2011b). Specific antibodies against FLAG epitope (M2) and vinculin (Sigma, St. Louis, MO, USA); anti-ERa (HC-20) anti-Bcl-2 (C-2) and anti-ubiquitin (P4D1) (Santa Cruz Biotechnology, Santa Cruz, CA, USA) were used.…”

Section: Cell Culture and Reagentsmentioning

confidence: 99%

“…The reporter plasmid 3xERE TATA, protein complement 3 (pC3) and the pXP2-D1-2966 plasmid (pD1) and the pcDNA FLAG-ERa have been described (La Rosa et al, 2011b). The pEGFP-ERa was obtained by subcloning the ERa ORF from the pSG5-HE0 (Acconcia et al, 2005a) into the pEGFP-C2 obtained by Dr Simona Polo, IFOM, Milan.…”

Section: Plasmids and Constructsmentioning

confidence: 99%

“…Pull-down experiments were performed as previously reported (La Rosa et al, 2011b;Penengo et al, 2006) by incubating 30 mg of GSTfusion proteins with either 300 mg of growing HeLa cells total lysate for 3 hours at 4˚C or with 0.5 mg of polyUb2-7 linked by Lys63 (Boston Biochem) for 1 hour at 4˚C in the presence of 20 mM E2. All experiments were normalized by running 1/ 10 of the pull-down on an SDS-PAGE gel.…”

Section: Plasmids and Constructsmentioning

confidence: 99%

“…Polyubiquitination controls the E2-dependent regulation of 26S-proteasome ERa degradation, which is interlaced with ERa transcriptional activity (La Rosa and Acconcia, 2011;La Rosa et al, 2012). Non-proteolytic Ub functions in E2:ERa signalling also occur and depend on ERa monoubiquitination, which is negatively modulated by E2 and controls E2-dependent cell proliferation (Eakin et al, 2007;La Rosa et al, 2011a;La Rosa et al, 2011b;Ma et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Identification of an estrogen receptor alpha non-covalent ubiquitin binding surface: role in 17beta-estradiol-induced transcriptional activity

Pesiri

Rosa

Stano

et al. 2013

Journal of Cell Science

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SummaryUbiquitin (Ub)-binding domains (UBDs) located in Ub receptors decode the ubiquitination signal by non-covalently engaging the Ub modification on their binding partners and transduce the Ub signalling through Ub-based molecular interactions. In this way, inducible protein ubiquitination regulates diverse biological processes. The estrogen receptor alpha (ERa) is a ligand-activated transcription factor that mediates the pleiotropic effects of the sex hormone 17b-estradiol (E2). Fine regulation of E2 pleiotropic actions depends on E2-dependent ERa association with a plethora of binding partners and/or on the E2 modulation of receptor ubiquitination. Indeed, E2-induced ERa polyubiquitination triggers receptor degradation and transcriptional activity, and E2-dependent reduction in ERa monoubiquitination is crucial for E2 signalling. Monoubiquitinated proteins often contain UBDs, but whether non-covalent Ub-ERa binding could occur and play a role in E2-ERa signalling is unknown. Here, we report an Ub-binding surface within the ERa ligand binding domain that directs in vitro the receptor interaction with both ubiquitinated proteins and recombinant Ub chains. Mutational analysis reveals that ERa residues leucine 429 and alanine 430 are involved in Ub binding. Moreover, impairment of ERa association to ubiquitinated species strongly affects E2-induced ERa transcriptional activity. Considering the importance of UBDs in the Ub-based signalling network and the central role of different ERa binding partners in the modulation of E2-dependent effects, our discoveries provide novel insights into ERa activity that could also be relevant for ERa-dependent diseases.

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Section: Role Of Era-ubs In E2-induced Era Gene Transcriptionmentioning

confidence: 95%

Section: Cell Culture and Reagentsmentioning

confidence: 99%

Section: Plasmids and Constructsmentioning

confidence: 99%

Section: Plasmids and Constructsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Identification of an estrogen receptor alpha non-covalent ubiquitin binding surface: role in 17beta-estradiol-induced transcriptional activity

Pesiri

Rosa

Stano

et al. 2013

Journal of Cell Science

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Ubiquitin‐activating enzyme is necessary for 17β‐estradiol‐induced breast cancer cell proliferation and migration

et al. 2014

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The sex steroid hormone 17b-estradiol (E2) regulates breast cancer (BC) cell proliferation and migration through the activation of a plethora of signal transduction cascades (e.g., PI3K/ AKT activation) starting after E2 binding to the estrogen receptor alpha (ERa). The activity of the ubiquitin (Ub)-system modulates many physiological processes (e.g., cell proliferation and migration), and recently, a specific inhibitor (Pyr-41) of the Ub-activating enzyme (E 1 ), which works as the activator of the Ub-based signaling, has been identified to prevent the functions of the Ub-system. Here, by using Pyr-41, we studied the involvement of the Ub-system in E2-induced signaling to proliferation and migration of BC cells. Our data indicate that E 1 activity is involved in the E2:ERa signaling important for cell proliferation and migration through the modulation of the E2-evoked activation of the PI3K/AKT and the p38/MAPK pathways. These discoveries indicate a new molecular circuitry that can be further explored to define new opportunities for BC treatment. V C 2014 IUBMB Life, 66(8):578-585, 2014

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Selective binding of estrogen receptor α to ubiquitin chains

et al. 2016

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Ubiquitin (Ub)-binding domains (UBDs) noncovalently contact the Ub modification on binding partners. Ub possesses seven lysine (K) residues (i.e., K6, K11, K27, K29, K33, K48, and K63) that can be used to form different chains based on different Ub linkage types (e.g., monoubiquitination/polyubiquitination). Thus, different Ub-based signals exist and are decoded by UBDs. Recently, we have reported the existence of two Ub binding surfaces located within the estrogen receptor a (ERa) protein. We have shown that the leucine (L) 429 and alanine (A) 430 ERa residues direct noncovalent receptor binding to K63-based Ub chains in vitro. However, mutation of L429 and A430 residues did not completely abolish the ability of ERa to associate with Ub in cell lines. Thus, we evaluated the possibility that one or both ERa Ub binding surfaces could noncovalently interact with other Ub chains. Here, we report that ERa selectively binds to specific Ub chains based on different Ub linkages and that ERa monoubiquitination requires noncovalent ERa:Ub binding. Considering the importance of the UBD:Ub interaction in the initiation and progression of many diseases (e.g., cancer), our data provide novel insights into ERa functions that could be relevant to ERa-related diseases.

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17β-Estradiol-induced cell proliferation requires estrogen receptor (ER) α monoubiquitination

Cited by 32 publications

References 25 publications

Identification of an estrogen receptor alpha non-covalent ubiquitin binding surface: role in 17beta-estradiol-induced transcriptional activity

Identification of an estrogen receptor alpha non-covalent ubiquitin binding surface: role in 17beta-estradiol-induced transcriptional activity

Ubiquitin‐activating enzyme is necessary for 17β‐estradiol‐induced breast cancer cell proliferation and migration

Selective binding of estrogen receptor α to ubiquitin chains

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