Krüppel-like factor 4 exhibits antiapoptotic activity following gamma-radiation-induced DNA damage.
In response to gamma-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 gamma-irradiation and does so by inhibiting the transition from the G(1) to S and G(2) to M phases of the cell cycle. Here, we determined the role of KLF4 in modulating the apoptotic response following gamma-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 gamma-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, p21(WAF1/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 gamma-radiation-induced DNA damage.
Ghaleb
A M
AM
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Katz
J P
JP
Kaestner
K H
KH
Du
J X
JX
Yang
V W
VW
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D019556:COS Cells; D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004249:DNA Damage; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics / Q000528:radiation effects*; D005434:Flow Cytometry; D005720:Gamma Rays; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology* / Q000528:radiation effects; D011401:Promoter Regions, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000528:radiation effects; D051028:bcl-2-Associated X Protein / Q000235:genetics
D017931:DNA Primers; D004273:DNA, Neoplasm; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein