Role for Krüppel-Like Factor 4 in Determining the Outcome of p53 Response to DNA Damage

Abstract

Cells are incessantly exposed to many sources of genotoxic stress. A critical unresolved issue is how the resulting activation of the p53 tumor suppressor can lead to either cell cycle arrest or apoptosis depending on the extent of DNA damage. The present study shows that the level of Krüppel-like factor 4 (KLF4) expression is inversely correlated with the extent of DNA damage. KLF4 is activated by p53 following cytostatic, mild DNA damage, whereas it is strongly repressed via enhanced turnover of mRNA on severe DNA damage that irreversibly drives cells to apoptosis. Blocking the repression of KLF4 on severe DNA damage suppresses p53-mediated apoptosis, whereas ablation of the KLF4 induction on mild DNA damage shifts the p53 response from cell cycle arrest to cell death. Our results suggest that coordinate regulation of KLF4 expression depending on the extent of DNA damage may be an important mechanism that dictates the life and death decisions of p53. [Cancer Res 2009;69(21):8284-92]

Peroxisome Proliferator-activated Receptor γ Agonists Induce Cell Cycle Arrest through Transcriptional Regulation of Krüppel-like Factor 4 (KLF4)

“…Plasmid Construction-DNA fragments of the KLF4 and PPAR␥ cDNA coding regions were amplified by PCR and subcloned into the pCDE-HA vector as described previously (26). For generation of the KLF4 promoter-reporters, the KLF4 Ϫ2051/ϩ252 (designated as P1) and Ϫ1597/ϩ252 (designated as P2) sequences were PCR-amplified and subcloned into the pGL3-Basic vector.…”

“…Reporter Assay-Luciferase assay was performed using the Dual-Luciferase reporter assay system (Promega) as described (26). HCT116 cells were transfected with pGL3-Basic (control) or KLF4 gene promoter constructs; 24 h after transfection, cells were left untreated or treated with 10 M TGZ for 18 h. Luciferase activity was then determined and normalized to an internal cytomegalovirus-Renilla luciferase control.…”

Kruppel-like factor 4 blocks tumor cell proliferation and promotes drug resistance in multiple myeloma

“…with a KLF4 signal ≥mean value + 2 SD in normal BMPC) and 30% of the patients had a very weak KLF4 signal <100. The KLF4 gene was not expressed by any of 18 HMCL (median value 5, range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Using western blot analysis, KLF4 protein could be detected in the five samples of purified primary MMC in which the KLF4 gene was expressed (Online Supplementary Figure S1B).…”

Regulation of Krüppel-like Factor 4 by the Anaphase Promoting Complex Pathway Is Involved in TGF-β Signaling

“…In addition, KLF4 can be induced by a variety of stimuli, including serum starvation (19,20), oxidative stress (21), sodium butyrate (22), selenium (23), interferon-␥ (IFN-␥) (24), and cAMP (25). Interestingly, KLF4 expression can be either elevated or repressed depending on the extent of DNA damage (26). Stimuli-elicited KLF4 regulation is known to be governed by multiple mechanisms including increased transcription, decreased mRNA stability, and increased protein stability.…”