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Ubiquitin–proteasome degradation of KLF5 transcription factor in cancer and untransformed epithelial cells

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Abstract

Ubiquitin-mediated proteolysis plays a central role in controlling intracellular levels of essential regulatory molecules such as p53, cyclins, myc, BRCA1, HIF-1α, etc. The Kruppel-like factor 5 (KLF5) transcription factor regulates biological processes involved in carcinogenesis, angiogenesis, and smooth muscle cell differentiation. In carcinogenesis, KLF5's role has been indicated by frequent genetic deletion as well as functional studies. Here we show that KLF5 is an unstable protein with a short half-life. Destruction of KLF5 was prevented by each of the proteasome-specific inhibitors tested but not by an inhibitor for trypsin-like proteases and cysteine proteases or by a lysosome inhibitor in epithelial cells. Furthermore, KLF5 underwent ubiquitination, and deletion of a 56-amino-acid sequence adjacent to a known transactivation domain of KLF5 significantly reduced its ubiquitination and degradation. Interestingly, cancer cells appeared to be more active in KLF5 degradation than untransformed epithelial cells, yet their proteasome activity was not higher. These results suggest that KLF5 protein is degraded at least in part through ubiquitination–proteasome pathway, which may have become hyperactive for KLF5 in cancer cells.

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Acknowledgements

We thank Dr Jun Zhou for providing the HA-Ub expression plasmid and Dr Shi-Yong Sun for valuable discussions. C Chen is an AFUD/AUA Research Scholar. This work was supported in part by NIH Grant CA87921 from the National Cancer Institute, by the Georgia Cancer Coalition, and by Grant DAMD17-03-2-0033 from the Department of Defense Prostate Cancer Research Program.

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Authors and Affiliations

  1. Department of Oncology and Hematology, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA, USA

    Ceshi Chen, Xiaodong Sun, Qimei Ran, Jonathan W Simons & Jin-Tang Dong

  2. Department of Biochemistry, Emory University School of Medicine, 4017 Rollins Research Building, Atlanta, GA, USA

    Keith D Wilkinson

  3. Department of Pharmacology, Emory University School of Medicine, 5031 Rollins Research Building, Atlanta, GA, USA

    T J Murphy

  4. Department of Urology and Program in Genetics and Molecular Biology, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA, USA

    Jin-Tang Dong

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  1. Ceshi Chen
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  2. Xiaodong Sun
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  3. Qimei Ran
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  4. Keith D Wilkinson
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Correspondence to Jin-Tang Dong.

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Chen, C., Sun, X., Ran, Q. et al. Ubiquitin–proteasome degradation of KLF5 transcription factor in cancer and untransformed epithelial cells. Oncogene 24, 3319–3327 (2005). https://doi.org/10.1038/sj.onc.1208497

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  • DOI: https://doi.org/10.1038/sj.onc.1208497

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