The F-box protein Fbl10 is a novel transcriptional repressor of c-Jun

Abstract

c-Jun is a component of the heterodimeric transcription factor AP-1 that is rapidly activated in response to ultraviolet light (UV)1. In unstressed cells, c-Jun activity is negatively regulated by transcriptional repressor complexes. Here we show that the F-box protein Fbl10/JHDM1B interacts with c-Jun and represses c-Jun-mediated transcription. Chromatin-immunoprecipitation assays demonstrate that Fbl10 is present at the c-jun promoter, and that c-Jun is required for the recruitment of Fbl10. Fbl10 binds to the unmethylated CpG sequences in the c-jun promoter through the CxxC zinc finger and tethers transcriptional repressor complexes. Suppression of Fbl10 expression by RNA interference (RNAi) induces transcription of c-jun and other c-Jun-target genes, and causes an aberrant cell-cycle progression and increased UV-induced cell death. Furthermore, Fbl10 protein and messenger RNA are downregulated in response to UV in an inverse correlation with c-Jun. Taken together, our results demonstrate that Fbl10 is a key regulator of c-Jun function.

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Figure 1: Fbl10 interacts with c-Jun.
Figure 2: Fbl10 is present at the c-jun promoter and binds to the unmethylated CpG sequences present in the c-jun promoter.
Figure 3: Fbl10 interacts with Sin3A and represses c-Jun-mediated transcription.
Figure 4: Fbl10 is a transcriptional repressor of c-Jun.
Figure 5: Fbl10 controls cell death and cell-cycle progression.

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Acknowledgements

We are grateful to M. Pagano in whose laboratory this work was initiated. We thank A. Behrens, D. Bohmann, Z. Ronai, R. Wisdom, Y. Xiong for reagents, D. Frescas, D. Guardavaccaro and S. Ottosen for their contributions to this work, H. Kato for helpful discussions, T. Bashir, M. J. Garabedian, J. Ohlmeyer, A. Peschiaroli and Z. Ronai for critical reading of the manuscript. This work was supported by a Bernard B. Levine Foundation award to R.K-N., a grant from the Mathers Charitable Foundation to N.T. and grants from the NIH.

Author information

R.K-N. carried out most of the experiments shown in Figs 1,2,3,4 and the Supplementary figures. G. D. performed the Sin3A experiments. N. T. supervised the work. R.K-N. wrote the paper with editing from N.T.

Correspondence to Ryo Koyama-Nasu.

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The authors declare no competing financial interests.

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Supplementary figures S1, S2, S3, S4, S5 and S6 (PDF 681 kb)

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Supplementary Methods (PDF 114 kb)

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Koyama-Nasu, R., David, G. & Tanese, N. The F-box protein Fbl10 is a novel transcriptional repressor of c-Jun. Nat Cell Biol 9, 1074–1080 (2007). https://doi.org/10.1038/ncb1628

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