Krüppel-like Factor 4 (Gut-enriched Krüppel-like Factor) Inhibits Cell Proliferation by Blocking G1/S Progression of the Cell Cycle

Abstract

Krü ppel-like factor 4 (KLF4) is an epithelial cell-enriched, zinc finger-containing transcription factor, the expression of which is associated with growth arrest. Previous studies show that constitutive expression of KLF4 inhibits DNA synthesis but the manner by which KLF4 exerts this effect is unclear. In the present study, we developed a system in which expression of KLF4 is controlled by a promoter that is induced upon treatment of cells containing the receptors for the insect hormone, ecdysone, with ponasterone A, an ecdysone analogue. The rate of proliferation of a stably transfected colon cancer cell line, RKO, was significantly decreased following addition of ponasterone A when compared with untreated cells. Flow cytometric analyses indicated that the inducible expression of KLF4 caused a block in the G 1 /S phase of the cell cycle. A similar block was observed when ecdysone receptor-containing RKO cells were infected with a replication-defective recombinant adenovirus containing an inducible KLF4 and treated with ponasterone A. Results of these studies provide evidence that the inhibitory effect of KLF4 on cell proliferation is mainly exerted at the G 1 /S boundary of the cell cycle.

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

“…In contrast, levels of KLF4 were significantly increased upon induction in both the unirradiated and irradiated states (lanes 3 and 4). The levels of p21 WAF1/CIP1 correlated with those of KLF4, consistent with previous results showing that p21 WAF1/CIP1 is a target of KLF4 (Zhang et al, 2000;Chen et al, 2001). BAX level was significantly increased in uninduced cells that had been irradiated (compare lane 2 to 1).…”

“…We previously established a derivative of RKO cells containing a stably transfected KLF4 cDNA under the control of an inducible promoter that responds to the insect hormone, ecdysone. This cell line, called EcR-RKO/pAdLoxEGI-KLF4 (Chen et al, 2001), produced a significant amount of KLF4 when treated with the inducer, ponasterone A. EcR-RKO/ pAdLoxEGI-KLF4 cells were irradiated, or not, with 12 Gy of g-ray and maintained in the presence of ponasterone A, or not, for 72 h before being processed for fluorescence-activated cell sorting (FACS) analysis. Figure 1 shows that in the absence of KLF4 induction, an appreciable number of cells contained DNA in the sub-G 1 fraction following irradiation (compare lane 2 with 1).…”

KLF4, p21 and context-dependent opposing forces in cancer

“…117). Also, KLF4 and Notch signalling regulate common cellular processes as well as transcriptional targets, particularly CDKN1A 23,24,118 . For example, mice deficient for one of multiple components of the Notch pathway develop an increased number of secretory cells, including goblet cells 119,120 , whereas activation of the Notch pathway results in a complete lack of development of goblet cells 121,122 .…”

“…13) and KLF7 (REF. 18)), KLF4 activates transcription of CDKN1A 23,24 . The functional status of p21 (also known as CIP1, WAF1, CAP20 or SDI1 ) seems to be intimately related to KLF4's function as either an anti-proliferative or, rather, a transforming gene.…”

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

“…Interestingly, maintaining elevated levels of KLF4 prevents apoptosis mediated by p53 (Ghaleb et al, 2007), and elimination of KLF4 induction leads to apoptosis in cells treated with nonapoptotic doses of DNA-damaging agents (Zhou et al, 2009). KLF4 activates CDKIs, p21, p27 and p57 (Chen et al, 2001Wei et al, 2006;Swamynathan et al, 2008); in particular, it cooperates with p53 in activating p21 (Zhang et al, 2000). KLF4 represses p53 transcription by binding to GC boxes in the p53 promoter: under these conditions, the levels of p21 and Cyclin D1 are crucial for deciding as to whether KLF4 exerts a tumor suppressive-high p21 or oncogenic-high Cyclin D1 activity (Rowland et al, 2005).…”