Ubiquitination-Mediated p57<sup>Kip2</sup> Degradation by CSN5 Confers Cancer Cell Proliferation

Zhao, Ruiying; Phan, Liem; Su, Chun-Hui; Chen, Bin; Yang, Heng-Yin; Chen, Jian; Che, Ting-Fang; Qiao, Yi; Zhang, Jin; Yeung, Sai‐Ching Jim; Lee, Mong‐Hong

doi:10.1166/ch.2013.1013

Cited by 9 publications

(11 citation statements)

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“…Total cell lysates were processed as previously decribed (42) (43, 44). Cell lysates for western blot or immunoprecipitation were collected from tissue culture dishes after two rinses with cold PBS.…”

Section: Methodsmentioning

confidence: 99%

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Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

Fang

Yang

Zhou

et al. 2015

Molecular Cancer Therapeutics

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Biomarkers for predicting chemotherapy response are important to treatment of colorectal cancer (CRC) patients. Cryptochrome 2 (CRY2) is a circadian clock protein involved in cell cycle, but the biological consequences of this activity in cancer are poorly understood. We set up biochemical and cell biology analyses to analyze CRY2 expression and chemoresistance. Here we report that CRY2 is overexpressed in chemoresistant CRC samples, and CRY2 overexpression is correlated with poor patient survival. Knockdown CRY2 increased colorectal cancer sensitivity to oxaliplatin in colorectal cancer cell. We also identify FBXW7 as a novel E3 ubiquitin ligase for targeting CRY2 through proteasomal degradation. Mechanistic studies show that CRY2 is regulated by FBXW7, in which FBXW7 binds directly to phosphorylated Thr300 of CRY2. Furthermore, FBXW7 expression leads to degradation of CRY2 through enhancing CRY2 ubiquitination and accelerating CRY2’s turnover rate. High expressed FBXW7 downregulates CRY2 and increases colorectal cancer cells sensitivity to chemotherapy. Low FBXW7 expression is correlated with high CRY2 expression in CRC patient samples. Also, low FBXW7 expression is correlated with poor patient survival. Taken together, our findings indicate that the upregulation of CRY2 caused by downregulation of FBXW7 may be a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer.

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Section: Methodsmentioning

confidence: 99%

“…Ubiquitination was processed as previously described (34, 43). DLD-1 cells cotransfected with indicated plasmids.…”

Section: Methodsmentioning

confidence: 99%

Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

Fang

Yang

Zhou

et al. 2015

Molecular Cancer Therapeutics

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“…The COP9 signalosome (CSN) is a multiprotein complex involved in protein degradation, transcriptional activation (Seeger et al, 1998; Wei and Deng, 1999), signal transduction (Chen et al, 2012; Xue et al, 2012; Zhang et al, 2008), and tumorigenesis (Chen et al, 2014; Richardson and Zundel, 2005; Zhao et al, 2014; Zhao et al, 2013; Zhao et al, 2011). However, the detailed biological functions of the CSN’s subunits have not been well characterized.…”

Section: Introductionmentioning

confidence: 99%

ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development

Fang

Choi

et al. 2015

Cancer Cell

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SUMMARY Biomarkers for predicting prognosis are critical to treating colorectal cancer (CRC) patients. We found that CSN6, a subunit of COP9 signalosome, is overexpressed in CRC samples and that CSN6 overexpression is correlated with poor patient survival. Mechanistic studies revealed that CSN6 is deregulated by EGFR signaling, in which ERK2 binds directly to CSN6 Leu163/Val165 and phosphorylates CSN6 at Ser148. Furthermore, CSN6 regulated β-Trcp and stabilizes β-catenin expression by blocking the ubiquitin-proteasome pathway, thereby promoting CRC development. High CSN6 expression was positively correlated with ERK2 activation and β-catenin overexpression in CRC samples, and inhibiting CSN6 stability with cetuximab reduced colon cancer growth. Taken together, our study’s findings indicate that the deregulation of β-catenin by ERK2-activated CSN6 is important for CRC development.

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“…5,[8][9][10][11] The role of the CSN's subunits in cancer has not been well characterized. We previously showed that Csn6¡/¡ mice developed until 7.5 d post-coitus.…”

Section: Introductionmentioning

confidence: 99%

Regulating the stability and localization of CDK inhibitor p27^Kip1 via CSN6-COP1 axis

et al. 2015

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The COP9 signalosome subunit 6 (CSN6), which is involved in ubiquitin-mediated protein degradation, is overexpressed in many types of cancer. CSN6 is critical in causing p53 degradation and malignancy, but its target in cell cycle progression is not fully characterized. Constitutive photomorphogenic 1 (COP1) is an E3 ubiquitin ligase associating with COP9 signalosome to regulate important target proteins for cell growth. p27 is a critical G1 CDK inhibitor involved in cell cycle regulation, but its upstream regulators are not fully characterized. Here, we show that the CSN6-COP1 link is regulating p27(Kip1) stability, and that COP1 is a negative regulator of p27(Kip1). Ectopic expression of CSN6 can decrease the expression of p27(Kip1), while CSN6 knockdown leads to p27(Kip1) stabilization. Mechanistic studies show that CSN6 interacts with p27(Kip1) and facilitates ubiquitin-mediated degradation of p27(Kip1). CSN6-mediated p27 degradation depends on the nuclear export of p27(Kip1), which is regulated through COP1 nuclear exporting signal. COP1 overexpression leads to the cytoplasmic distribution of p27, thereby accelerating p27 degradation. Importantly, the negative impact of COP1 on p27 stability contributes to elevating expression of genes that are suppressed through p27 mediation. Kaplan-Meier analysis of tumor samples demonstrates that high COP1 expression was associated with poor overall survival. These data suggest that tumors with CSN6/COP1 deregulation may have growth advantage by regulating p27 degradation and subsequent impact on p27 targeted genes.

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Ubiquitination-Mediated p57^Kip2 Degradation by CSN5 Confers Cancer Cell Proliferation

Cited by 9 publications

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Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development

Regulating the stability and localization of CDK inhibitor p27^Kip1 via CSN6-COP1 axis

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Ubiquitination-Mediated p57Kip2 Degradation by CSN5 Confers Cancer Cell Proliferation

Cited by 9 publications

References 0 publications

Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development

Regulating the stability and localization of CDK inhibitor p27Kip1 via CSN6-COP1 axis

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Product

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Ubiquitination-Mediated p57^Kip2 Degradation by CSN5 Confers Cancer Cell Proliferation

Regulating the stability and localization of CDK inhibitor p27^Kip1 via CSN6-COP1 axis