Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1

Li, Chao; Ao, Junping; Fu, Junjiang; Lee, Dung‐Fang; Xu, Jianming; Lonard, David M.; O’Malley, Bert W.

doi:10.1038/onc.2011.151

Cited by 151 publications

(150 citation statements)

References 69 publications

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“…Overexpression of SPOP resulted in suppression of cell proliferation, arrest of cell migration. This evidence suggests a potential role for SPOP in the regulation of glioma cell growth and proliferation which are in agreement with previous studies (11).…”

Section: Discussionsupporting

confidence: 93%

“…Considering pro-apoptotic and other tumor-suppressive functions of SPOP identified in earlier studies (11,29), we suggest that downregulation of SPOP in the cancers compared with normal cells might possibly decrease its functions as a tumor suppressor gene and might contribute to cancer development. Although most of the identified functions of SPOP are related to tumor suppression, there is evidence that SPOP serves as a regulatory hub to promote clear cell renal cell carcinoma (ccRCC) tumorigenesis suggesting a possibility that tumor-related functions of SPOP might vary depending on tissue and cellular contexts (30).…”

Section: Discussionmentioning

confidence: 65%

“…Ubiquitin modifications regulate a wide variety of cellular processes and more or less are involved in cancer pathogenesis (10). Also, earlier observations that SPOP, an adaptor for Cul3-based ubiquitination (6)(7)(8)(9)(10)(11), may be a TSG led us to further analyze whether SPOP gene mutations occurred in other common malignancies. In one recent study, we found that only 0.2% of hematologic malignancies and none of the solid tumors (breast, lung and liver cancers) harbored SPOP somatic mutations, suggesting that somatic mutation of SPOP gene may not play a role in the development of breast, lung, and liver cancers, and acute leukemias.…”

Section: Introductionmentioning

confidence: 99%

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Decreased expression of the SPOP gene is associated with poor prognosis in glioma

Ding

Song

et al. 2014

International Journal of Oncology

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Abstract. This study suggests that speckle-type POZ protein (SPOP) may be a tumor suppressor gene and its prognostic value in human glioma. Real-time quantitative RT-PCR (qRT-PCR), western blotting, and immunohistochemical staining were used to examine SPOP expression in glioma tissues and normal brain (NB) tissues. The relationships between the SPOP expression levels, the clinicopathological factors, and patient survival were investigated. The molecular mechanisms of SPOP expression and its effects on cell viability, migration and invasion were also explored by MTT assay, wound-healing assays and Transwell assay. SPOP mRNA and protein levels were downregulated in glioma tissues compared to NB. Immunohistochemical staining results showed low expression in 62.2% (61/98) of glioma samples, while high expression in 75% (9/12) of NB samples, and the difference was statistically significant (P=0.014). In addition, decreased SPOP was associated disease progression in glioma samples, the expression level of SPOP was positively correlated with mean tumor diameter (MTD) (P= 0.021) and the status of tumor grade and histological type (WHO I, II, III and IV) (P= 0.032) in glioma patients. Additionally, the overall survival of patients with low SPOP expression was significantly worse than that of SPOP-high patients (P= 0.001). In vitro overexpression of SPOP markedly inhibited cell viability, migration and invasion in vitro. These findings suggest that SPOP has potential use as novel biomarker of glioma and may serve as an independent predictive factor for prognosis of glioma patients.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

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Decreased expression of the SPOP gene is associated with poor prognosis in glioma

Ding

Song

et al. 2014

International Journal of Oncology

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“…PP1 overexpression was able to inhibit the reporter activity as well as the cell proliferative ability of AIB1. The Ser 102 site is also a site of regulation by the ubiquitin ligase SPOP (64). This site is lost in AIB1-⌬4 and could explain the high coactivator activity and stability of the AIB1-⌬4 protein.…”

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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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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“…When this manuscript was submitted, another study was issued, reporting also a role for a CRL3 complex in SRC-3 ubiquitination and proteolysis (23). However, in this study, CUL-3 was recruited through the BTB protein SPOP (speckle-typePOZ protein) to a different motif that was phosphorylated by a different kinase.…”

Section: Src-3 Degradation By a Cul-3-based E3 Ligase Contributes To Thementioning

confidence: 95%

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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Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1

Cited by 151 publications

References 69 publications

Decreased expression of the SPOP gene is associated with poor prognosis in glioma

Decreased expression of the SPOP gene is associated with poor prognosis in glioma

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

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

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