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

被引:96
作者
Ghaleb, A. M.
Katz, J. P.
Kaestner, K. H.
Du, J. X.
Yang, V. W.
机构
[1] Emory Univ, Sch Med, Dept Med, Div Digest Dis, Atlanta, GA 30322 USA
[2] Univ Penn, Sch Med, Dept Med, Div Gastroenterol, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA
[4] Emory Univ, Sch Med, Winship Canc Inst, Dept Hematol & Oncol, Atlanta, GA 30322 USA
关键词
apoptosis; cell cycle; KLF4; p53; BAX; p21(WAF1/CIP1); P53; TUMOR-SUPPRESSOR; CELL-CYCLE ARREST; APOPTOSIS; GENE; KLF4; DIFFERENTIATION; IDENTIFICATION; PROLIFERATION; EXPRESSION; PROGRESSION;
D O I
10.1038/sj.onc.1210022
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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, Kruppel-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 G1 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 c-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.
引用
收藏
页码:2365 / 2373
页数:9
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