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Opposing functions of Fbxw7 in keratinocyte growth, differentiation and skin tumorigenesis mediated through negative regulation of c-Myc and Notch

Oncogene volume 32, pages 1921–1932 (2013)Cite this article

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Abstract

The tumor suppressor Fbxw7 (also known as Sel-10, hCdc4, hAgo, or Fbw7) is an F-box protein that functions as the substrate-recognition subunit of an SCF ubiquitin ligase complex and targets a group of oncoproteins for degradation. We now show that Fbxw7 regulates the proliferation and differentiation of keratinocytes by mediating the degradation of c-Myc and Notch proteins. Fbxw7-deficient keratinocytes showed an increased proliferative capacity that was dependent on the accumulation of c-Myc but not on that of Notch. Fbxw7 deficiency also resulted in the premature differentiation of keratinocytes in a manner dependent on both c-Myc and Notch. Although Fbxw7-deficient keratinocytes proliferated excessively in vitro, loss of Fbxw7 did not predispose keratinocytes to the formation of squamous cell carcinoma in vivo induced by the expression of oncogenic Ras, possibly because the stem cell population of keratinocytes becomes exhausted as a result of enhanced Notch activity. Indeed, suppression of Notch signaling by additional ablation of RBP-J in Fbxw7-deficient keratinocytes conferred a more aggressive tumorigenic capacity. Collectively, these results indicate that Fbxw7 controls the proliferation and differentiation of keratinocytes, and that it exerts both inhibitory and stimulatory actions in skin carcinogenesis by counteracting the proliferation-promoting effect of c-Myc and the tumor-suppressive effect of Notch, respectively.

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Acknowledgements

We thank T Honjo for RbpjF/F mice; IM de Alborán for c-MycF/F mice; R Tsunematsu for the NICD1 plasmid; T Kitamura for pMX-puro and Plat-E cells; Y Gotoh for pMX-Cre-SV40-GFP; S Ikawa for the cDNA-encoding H-RasG12V; E Ogawa and E Nishimura for technical advice; Y Ono, T Senga and N Yanagihara for technical assistance; and other laboratory members for discussion. This study was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by the Global Center of Excellence Program of Japan.

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Authors and Affiliations

  1. Department of Cell Proliferation, United Center for Advanced Research and Translational Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan

    Y Ishikawa, M Hosogane, S Aoyama & K Nakayama

  2. CREST, Japan Science and Technology Agency, Kawaguchi, Japan

    Y Ishikawa, M Hosogane, S Aoyama, I Onoyama, K I Nakayama & K Nakayama

  3. Department of Dermatology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan

    R Okuyama

  4. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    I Onoyama & K I Nakayama

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  1. Y Ishikawa
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Correspondence to K Nakayama.

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Ishikawa, Y., Hosogane, M., Okuyama, R. et al. Opposing functions of Fbxw7 in keratinocyte growth, differentiation and skin tumorigenesis mediated through negative regulation of c-Myc and Notch. Oncogene 32, 1921–1932 (2013). https://doi.org/10.1038/onc.2012.213

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