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Krüppel-like factor 4 exhibits antiapoptotic activity following γ-radiation-induced DNA damage

Oncogene volume 26, pages 2365–2373 (2007)Cite this article

Abstract

In response to γ-radiation-induced DNA damage, organisms either activate cell cycle checkpoint and repair machinery or undergo apoptosis to eliminate damaged cells. Although previous studies indicated that the tumor suppressor p53 is critically involved in mediating both responses, how a cell decides which pathway to take is not well established. The zinc-finger-containing transcription factor, Krüppel-like factor 4 (KLF4), is a crucial mediator for the checkpoint functions of p53 after γ-irradiation and does so by inhibiting the transition from the G1 to S and G2 to M phases of the cell cycle. Here, we determined the role of KLF4 in modulating the apoptotic response following γ-irradiation. In three independent cell systems including colorectal cancer cells and mouse embryo fibroblasts in which expression of KLF4 could be manipulated, we observed that γ-irradiated cells underwent apoptosis if KLF4 was absent. In the presence of KLF4, the degree of apoptosis was significantly reduced and cells resorted to checkpoint arrest. The mechanism by which KLF4 accomplished this antiapoptotic effect is by activating expression of the cell cycle arrest gene, p21WAF1/CIP1, and by inhibiting the ability of p53 to transactivate expression of the proapoptotic gene, BAX. Results of our study illustrate an unexpected antiapoptotic function of KLF4, heretofore considered a tumor suppressor in colorectal cancer, and suggest that KLF4 may be an important determinant of cell fate following γ-radiation-induced DNA damage.

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Abbreviations

bp:

base pair

ChIP:

chromatin immunoprecipitation

DMEM:

Dulbecco's modified Eagle's medium

FACS:

fluorescence-activated cell sorting

FBS:

fetal bovine serum

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

KLF4:

Krüppel-like factor 4

MEFs:

mouse embryo fibroblasts

nt:

nucleotide

PBS:

phosphate-buffered saline

shRNA:

small hairpin RNA

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Acknowledgements

We thank B Vogelstein for providing the pC53-SN3 expression construct and the HCT116BAX−/− and p21WAF1/CIP1−/− cell lines. This work was in part supported by grants from the National Institutes of Health (DK52230, DK64399 and CA84197). VWY is the recipient of a Georgia Cancer Coalition Distinguished Cancer Clinician Scientist Award.

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Authors and Affiliations

  1. Division of Digestive Diseases, Department of Medicine,

    A M Ghaleb, J X Du & V W Yang

  2. Emory University School of Medicine, Atlanta, GA, USA

    A M Ghaleb, J X Du & V W Yang

  3. Division of Gastroenterology, Department of Medicine,

    J P Katz

  4. University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    J P Katz

  5. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    K H Kaestner

  6. Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    V W Yang

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  1. A M Ghaleb
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Corresponding author

Correspondence to V W Yang.

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

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Ghaleb, A., Katz, J., Kaestner, K. et al. Krüppel-like factor 4 exhibits antiapoptotic activity following γ-radiation-induced DNA damage. Oncogene 26, 2365–2373 (2007). https://doi.org/10.1038/sj.onc.1210022

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