E6AP Mediates Regulated Proteasomal Degradation of the Nuclear Receptor Coactivator Amplified in Breast Cancer 1 in Immortalized Cells

Mani, Aparna; Oh, Annabell S.; Bowden, Emma T.; Lahusen, Tyler; Lorick, Kevin L.; Weissman, Allan M.; Schlegel, Richard; Wellstein, Anton; Riegel, Anna T.

doi:10.1158/0008-5472.can-06-0557

Cited by 63 publications

(61 citation statements)

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“…We have previously shown that AIB1 protein levels are greatly reduced in response to growth of cells at high confluence and the removal of growth factors (62). Interestingly, we found that the AIB1-⌬4 isoform is not regulated in the same fashion as AIB1 protein (supplemental Fig.…”

Section: Discussionmentioning

confidence: 63%

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Role of the Nuclear Receptor Coactivator AIB1-Δ4 Splice Variant in the Control of Gene Transcription

Chien

Kirilyuk

et al. 2011

Journal of Biological Chemistry

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The oncogene amplified in breast cancer 1 (AIB1) is a nuclear receptor coactivator that plays a major role in the progression of various cancers. We previously identified a splice variant of AIB1 called AIB1-⌬4 that is overexpressed in breast cancer. Using mass spectrometry, we define the translation initiation of AIB1-⌬4 at Met 224 of the full-length AIB1 sequence and have raised an antibody to a peptide representing the acetylated N terminus. We show that AIB1-⌬4 is predominantly localized in the cytoplasm, although leptomycin B nuclear export inhibition demonstrates that AIB1-⌬4 can enter and traffic through the nucleus. Our data indicate an import mechanism enhanced by other coactivators such as p300/CBP. We report that the endogenously and exogenously expressed AIB1-⌬4 is recruited as efficiently as full-length AIB1 to estrogen-response elements of genes, and it enhances estrogen-dependent transcription more effectively than AIB1. Expression of an N-terminal AIB1 protein fragment, which is lost in the AIB1-⌬4 isoform, potentiates AIB1 as a coactivator. This suggests a model whereby the transcriptional activity of AIB1 is squelched by a repressive mechanism utilizing the N-terminal domain and that the increased coactivator function of AIB1-⌬4 is due to the loss of this inhibitory domain. Finally, we show, using Scorpion primer technology, that AIB1-⌬4 expression is correlated with metastatic capability of human cancer cell lines.Gene transcription in eukaryotes is a complex and highly regulated process. One of the major controls of gene transcription is exerted by the coregulator family of proteins. These include both corepressors, which dampen transcription, and coactivators, which potentiate transcription. A subgroup of coactivators has been shown to be critical for the malignant progression of cancer and is known as the p160 steroid receptor coactivators (1). One member in particular was identified to be amplified in breast cancer. Amplified in breast cancer 1 (AIB1, SRC-3, NCOA3, ACTR, TRAM-1, pCIP, and RAC3) has been shown to be a gene amplified in breast cancer (2) and is also overexpressed at the mRNA and protein level in various cancers (1, 3, 4). Its role in tumorigenesis is attributed to its ability to coactivate both steroid hormone-and growth factor-dependent transcription (3, 5-7). In several oncogene-driven mouse models (8 -11), reduction of AIB1 levels leads to a decrease in tumorigenesis, and overexpression of AIB1 leads to the formation of various tumors (12). Clinically, AIB1 expression in breast cancer cases is correlated with high HER2 levels, larger tumor size, higher tumor grade, and shorter disease-free survival (13-15). Also, high levels of AIB1 in conjunction with high HER2 levels coincide with reduced disease-free survival in patients treated with tamoxifen, suggesting a role for AIB1 in tamoxifen resistance (16).We had previously identified a splice variant of AIB1, where exon 3 was spliced from the mature mRNA and the resulting protein named AIB1-⌬3 (17). More recently, an additio...

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Section: Discussionmentioning

confidence: 63%

“…This is probably due to loss of a site of regulation in the N-terminal 223 amino acids. The proteasomal regulation of AIB1 has been well characterized (57,62,63). Interestingly, regulation of a phospho-degron at Ser 102 by protein phosphatase 1 (PP1) was shown to be important for regulating the activity of AIB1.…”

Section: Discussionmentioning

confidence: 99%

Role of the Nuclear Receptor Coactivator AIB1-Δ4 Splice Variant in the Control of Gene Transcription

Chien

Kirilyuk

et al. 2011

Journal of Biological Chemistry

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“…4D), thus likely reduces ubiquitin-mediated degradation, hence increases protein abundance. Because there are several ubiquitin-E3 ligases that can lead to degradation of NCOA3, including Fbw7␣, E6AP, and CHIP (47,(51)(52), it is not clear at the moment which one of them, or all of them, is sensitive to SUMO-induced resistance. It is also possible that sumoylation alters NCOA3 sensitivity toward ubiquitin-independent REG␥-mediated degradation of NCOA3 (49).…”

Section: Discussionmentioning

confidence: 99%

“…1B). It is known that NCOA3 protein level is subject to regulation through both ubiquitin-dependent and ubiquitin-independent mechanisms by REG␥ and aPKC as well as several ubiquitin E3 ligases, such as Fbw7␣, E6AP, and CHIP (47)(48)(49)(50)(51)(52). It is possible that SYT is less potent than SYT-SSX1 in increasing sumoylation of NCOA3, thus at certain cellular level of PIASy activity, SYT is no longer able to protect NCOA3 protein through sumoylation.…”

Section: Ssx1 (mentioning

confidence: 99%

SYT-SSX1 (Synovial Sarcoma Translocated) Regulates PIASy Ligase Activity to Cause Overexpression of NCOA3 Protein

Sun¹,

Perera

Rubin

et al. 2011

Journal of Biological Chemistry

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Chromosomal translocations are a major source of genetic abnormalities causally linked to certain malignancies. Synovial sarcoma is an aggressive soft tissue tumor characterized by a chromosomal translocation between chromosome 18 and X, generating oncoproteins such as SYT-SSX1 and SYT-SSX2. The molecular mechanism underlying the oncogenic potential of SYT-SSX1/2 is not clear. Here we show that SYT-SSX1 leads to up-regulation of NCOA3, a protein critical for the formation of various cancers. The increase of NCOA3 is essential for SYT-SSX1-mediated synovial sarcoma formation. SYT-SSX1 does so by increasing the sumoylation of NCOA3 through interaction with a SUMO E3 ligase, PIASy, as well as the sumoylation of NEMO. NEMO has also been shown to physically interact with NCOA3. Increased sumoylation of NCOA3 leads to its increased steady state level and nuclear localization. Our findings represent the first example that an oncoprotein directly regulates substrate modification by a SUMO E3 ligase, and leads to overexpression of a protein essential for tumor formation. Such a mechanistic finding provides an opportunity to design specific therapeutic interventions to treat synovial sarcoma.

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“…1F). However, the screen did not identify with high confidence any of the other E3 ligases (CUL-1-skp1-Fbw7α and E6AP) previously reported to regulate SRC-3 degradation (4,8) (Fig. 1F).…”

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confidence: 87%

Cullin 3 mediates SRC-3 ubiquitination and degradation to control the retinoic acid response

Ferry¹,

Gaouar²,

Fischer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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SRC-3 is an important coactivator of nuclear receptors including the retinoic acid (RA) receptor α. Most of SRC-3 functions are facilitated by changes in the posttranslational code of the protein that involves mainly phosphorylation and ubiquitination. We recently reported that SRC-3 is degraded by the proteasome in response to RA. Here, by using an RNAi E3-ubiquitin ligase entry screen, we identified CUL-3 and RBX1 as components of the E3 ubiquitin ligase involved in the RA-induced ubiquitination and subsequent degradation of SRC-3. We also show that the RA-induced ubiquitination of SRC-3 depends on its prior phosphorylation at serine 860 that promotes binding of the CUL-3–based E3 ligase in the nucleus. Finally, phosphorylation, ubiquitination, and degradation of SRC-3 cooperate to control the dynamics of transcription. In all, this process participates to the antiproliferative effect of RA.

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E6AP Mediates Regulated Proteasomal Degradation of the Nuclear Receptor Coactivator Amplified in Breast Cancer 1 in Immortalized Cells

Cited by 63 publications

References 50 publications

Role of the Nuclear Receptor Coactivator AIB1-Δ4 Splice Variant in the Control of Gene Transcription

Role of the Nuclear Receptor Coactivator AIB1-Δ4 Splice Variant in the Control of Gene Transcription

SYT-SSX1 (Synovial Sarcoma Translocated) Regulates PIASy Ligase Activity to Cause Overexpression of NCOA3 Protein

Cullin 3 mediates SRC-3 ubiquitination and degradation to control the retinoic acid response

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