title: KDM2B/FBXL10 targets c-Fos for ubiquitylation and degradation in response to mitogenic stimulation.
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/SCF(KDM2B)) 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.
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, People's Republic of China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shangai, People's Republic of China.|School of Life Sciences, Fudan University, Shangai, People's Republic of China.
authors.forename: X-R
authors.initials: XR
authors.lastname: Han
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, People's Republic of China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shangai, People's Republic of China.|School of Life Sciences, Fudan University, Shangai, People's Republic of China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zha
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, People's Republic of China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shangai, People's Republic of China.
authors.forename: H-X
authors.initials: HX
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, People's Republic of China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shangai, People's Republic of China.|School of Life Sciences, Fudan University, Shangai, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Feng
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, People's Republic of China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shangai, People's Republic of China.|School of Life Sciences, Fudan University, Shangai, People's Republic of China.
authors.forename: Y-K
authors.initials: YK
authors.lastname: Xia
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, People's Republic of China.|Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shangai, People's Republic of China.
authors.forename: Q-Y
authors.initials: QY
authors.lastname: Lei
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, People's Republic of China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shangai, People's Republic of China.|Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shangai, People's Republic of China.|Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
authors.forename: K-L
authors.initials: KL
authors.lastname: Guan
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, People's Republic of China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shangai, People's Republic of China.|School of Life Sciences, Fudan University, Shangai, People's Republic of China.|Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects*
chemical_list: D044783:F-Box Proteins; D008934:Mitogens; D016760:Proto-Oncogene Proteins c-fos; D004815:Epidermal Growth Factor; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D044767:Ubiquitin-Protein Ligases