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

Oncogene volume 30, pages 4350–4364 (2011)Cite this article

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Abstract

Steroid receptor co-activator-3 (SRC-3/AIB1) is an oncogene that is amplified and overexpressed in many human cancers. However, the molecular mechanisms that regulate ‘activated SRC-3 oncoprotein’ turnover during tumorigenesis remain to be elucidated. Here, we report that speckle-type POZ protein (SPOP), a cullin 3 (CUL3)-based ubiquitin ligase, is responsible for SRC-3 ubiquitination and proteolysis. SPOP interacts directly with an SRC-3 phospho-degron in a phosphorylation-dependent manner. Casein kinase Iɛ phosphorylates the S102 in this degron and promotes SPOP-dependent turnover of SRC-3. Short hairpin RNA knockdown and overexpression experiments substantiated that the SPOP/CUL3/Rbx1 ubiquitin ligase complex promotes SRC-3 turnover. A systematic analysis of the SPOP genomic locus revealed that a high percentage of genomic loss or loss of heterozygosity occurs at this locus in breast cancers. Furthermore, we demonstrate that restoration of SPOP expression inhibited SRC-3-mediated oncogenic signaling and tumorigenesis, thus positioning SPOP as a tumor suppressor.

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Acknowledgements

We thank Ming-Jer Tsai and Sophia Y Tsai for their suggestions and Dr Kevin White (University of Chicago) for the monoclonal antibodies against SPOP. This work was supported by funding from State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute and grants (81072163) from National Natural Science Foundation of China (CL), and NIH HD-08188 and HD-07857 grants (BWO).

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  1. C Li: These institutes in 1 and 2 contributed equally to this work.

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  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    C Li, J Fu, J Xu, D Lonard & B W O'Malley

  2. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    C Li & J Ao

  3. Department of Gene and Cell Medicine, Black Family Stem Cell Research Institute, Mount Sinai School of Medicine, New York, NY, USA

    D-F Lee

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Li, C., Ao, J., Fu, J. et al. Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1. Oncogene 30, 4350–4364 (2011). https://doi.org/10.1038/onc.2011.151

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