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Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells

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Abstract

Although Kruppel-like factor 5 (KLF5) is a transcription factor that has been implicated in pathways critical to carcinogenesis, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Here, we describe a novel role for KLF5 in a p53-independent apoptotic pathway. Using RNA-interference technology, we show that cells deficient in KLF5 have increased sensitivity to DNA damage, regardless of p53 status. Both p53 and p53-dependent factors are unaffected by KLF5 depletion. Instead, the apoptotic phenotype consequent to damage is associated with reduced bad phosphorylation, and downregulation of Pim1. Consistently, transfection of wild-type Pim1 is sufficient to rescue this phenotype. Previous data have shown a number of putative Sp1-binding consensus sequences on the Pim1 promoter. Remarkably, chromatin immunoprecipitation studies show that KLF5 binds to the Pim1 promoter, and that binding increases soon after damage. These results identify a novel, p53-independent apoptotic pathway through which KLF5 functions in response to DNA damage. Therapeutic deregulation of this pathway could be used to modulate chemosensitivity.

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Acknowledgements

We thank Dr B Vogelstein and P Koskinen for kindly providing reagents, and Drs M van der Heijden and A Thiagarajan for critically evaluating the manuscript. This project was funded by the Cancer Research and Education Fund from the National Cancer Centre, Singapore and through a Singhealth Foundation grant.

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Author notes

  1. Y Zhao and M S Hamza: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgical Oncology, Wee Kim Wee Laboratory of Surgical Oncology, National Cancer Centre, Singapore

    Y Zhao, H S Leong, C-B Lim, K-C Soo & N G Iyer

  2. Genome Institute of Singapore, Singapore

    M S Hamza, Y-F Pan & E Cheung

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  1. Y Zhao
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  2. M S Hamza
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  3. H S Leong
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  7. K-C Soo
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Correspondence to N G Iyer.

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Supplementary Information accompanies the paper on the Oncogene web site (http://www.nature.com/onc).

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Zhao, Y., Hamza, M., Leong, H. et al. Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells. Oncogene 27, 1–8 (2008). https://doi.org/10.1038/sj.onc.1210625

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  • DOI: https://doi.org/10.1038/sj.onc.1210625

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