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KDM2B/FBXL10 targets c-Fos for ubiquitylation and degradation in response to mitogenic stimulation

Oncogene volume 35, pages 4179–4190 (2016)Cite this article

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Abstract

KDM2B (also known as FBXL10) controls stem cell self-renewal, somatic cell reprogramming and senescence, and tumorigenesis. KDM2B contains multiple functional domains, including a JmjC domain that catalyzes H3K36 demethylation and a CxxC zinc-finger that recognizes CpG islands and recruits the polycomb repressive complex 1. Here, we report that KDM2B, via its F-box domain, functions as a subunit of the CUL1-RING ubiquitin ligase (CRL1/SCFKDM2B) complex. KDM2B targets c-Fos for polyubiquitylation and regulates c-Fos protein levels. Unlike the phosphorylation of other SCF (SKP1-CUL1-F-box)/CRL1 substrates that promotes substrates binding to F-box, epidermal growth factor (EGF)-induced c-Fos S374 phosphorylation dissociates c-Fos from KDM2B and stabilizes c-Fos protein. Non-phosphorylatable and phosphomimetic mutations at S374 result in c-Fos protein which cannot be induced by EGF or accumulates constitutively and lead to decreased or increased cell proliferation, respectively. Multiple tumor-derived KDM2B mutations impaired the function of KDM2B to target c-Fos degradation and to suppress cell proliferation. These results reveal a novel function of KDM2B in the negative regulation of cell proliferation by assembling an E3 ligase to targeting c-Fos protein degradation that is antagonized by mitogenic stimulations.

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Acknowledgements

We thank the members of the Fudan MCB laboratory for discussions and support throughout this study and Michele Pagano of NYU for providing plasmids expressing full-length human KDM2B cDNA. This work was supported by Chinese Ministry of Sciences and Technology 973 (Grant No. 2015CB910401), NSFC (Grant No. 81225016, 81430057), Shanghai Key basic research program (12JC1401100), Shanghai Outstanding Academic Leader (Grant No.13XD1400600) and the Youth Science and Technology Leading Talent by MOST (to Q-YL), NIH Grants EY022611 and CA132809 (to K-LG) and GM067113 (to YX).

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Authors and Affiliations

  1. Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, People's Republic of China

    X-R Han, Z Zha, H-X Yuan, X Feng, Y-K Xia, Q-Y Lei, K-L Guan & Y Xiong

  2. Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shangai, People's Republic of China

    X-R Han, Z Zha, H-X Yuan, X Feng, Y-K Xia, K-L Guan & Y Xiong

  3. School of Life Sciences, Fudan University, Shangai, People’s Republic of China

    X-R Han, Z Zha, X Feng, Y-K Xia & Y Xiong

  4. Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shangai, People's Republic of China

    Q-Y Lei & K-L Guan

  5. Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA

    K-L Guan

  6. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    Y Xiong

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  1. X-R Han
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Correspondence to Q-Y Lei, K-L Guan or Y Xiong.

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Han, XR., Zha, Z., Yuan, HX. et al. KDM2B/FBXL10 targets c-Fos for ubiquitylation and degradation in response to mitogenic stimulation. Oncogene 35, 4179–4190 (2016). https://doi.org/10.1038/onc.2015.482

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