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

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• KDM2B (FBXL10) is crucial for stem cell regulation, reprogramming, senescence, and tumorigenesis.
• KDM2B possesses JmjC and CxxC domains involved in H3K36 demethylation and CpG island recognition, respectively.
• KDM2B's role in ubiquitin ligase complexes was previously uncharacterized.

Purpose of the Study:

• To elucidate the function of KDM2B's F-box domain.
• To investigate KDM2B's role in regulating c-Fos protein levels and cell proliferation.
• To understand how mitogenic stimuli affect KDM2B-mediated c-Fos regulation.

Main Methods:

• Investigated KDM2B as a CUL1-RING ubiquitin ligase (CRL1/SCF(KDM2B)) subunit.
• Assessed KDM2B's targeting of c-Fos for polyubiquitylation and degradation.
• Utilized EGF stimulation and analyzed c-Fos phosphorylation at S374.
• Examined effects of S374 mutations and tumor-derived KDM2B mutations on cell proliferation.

Main Results:

• KDM2B functions as part of the CRL1/SCF(KDM2B) E3 ubiquitin ligase complex.
• KDM2B targets c-Fos for polyubiquitylation, regulating its protein levels.
• EGF-induced phosphorylation of c-Fos at S374 dissociates it from KDM2B, stabilizing c-Fos.
• Mutations impairing c-Fos degradation by KDM2B correlate with altered cell proliferation and tumor development.

Conclusions:

• KDM2B negatively regulates cell proliferation by targeting c-Fos for degradation via an E3 ligase complex.
• Mitogenic stimulation, like EGF, antagonizes KDM2B's tumor-suppressive function by stabilizing c-Fos.
• Dysregulation of KDM2B-mediated c-Fos degradation is implicated in tumorigenesis.