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Abstract
BackgroundWe previously reported that overexpression of Axin downregulates T cell factor-4 (TCF-4) transcription. However, the mechanism(s) by which Axin downregulates the transcription and expression of TCF-4 is not clear. It has been reported that β-catenin promotes and p53 inhibits TCF-4 transcription, respectively. The aim of this study was to investigate whether β-catenin and/or p53 is required for Axin-mediated downregulation of TCF-4.ResultsAxin mutants that lack p53/HIPK2 and/or β-catenin binding domains were expressed in lung cancer cells, BE1 (mutant p53) and A549 (wild type p53). Expression of Axin or AxinΔp53 downregulates β-catenin and TCF-4, and knock-down of β-catenin upregulates TCF-4 in BE1 cells. However, expression of AxinΔβ-ca into BE1 cells did not downregulate TCF-4 expression. These results indicate that Axin downregulates TCF-4 transcription via β-catenin. Although overexpression of wild-type p53 also downregulates TCF-4 in BE1 cells, cotransfection of p53 and AxinΔβ-ca did not downregulate TCF-4 further. These results suggest that Axin does not promote p53-mediated downregulation of TCF-4. Axin, AxinΔp53, and AxinΔβ-ca all downregulated β-catenin and TCF-4 in A549 cells. Knock-down of p53 upregulated β-catenin and TCF-4, but cotransfection of AxinΔβ-ca and p53 siRNA resulted in downregulation of β-catenin and TCF-4. These results indicate that p53 is not required for Axin-mediated downregulation of TCF-4. Knock-down or inhibition of GSK-3β prevented Axin-mediated downregulation of TCF-4. Furthermore, expression of Axin and AxinΔp53, prevented the proliferative and invasive ability of BE1 and A549, expression of AxinΔβ-ca could only prevented the proliferative and invasive ability effectively.ConclusionsAxin downregulates TCF-4 transcription via β-catenin and independently of p53. Axin may also inhibits the proliferation and invasion of lung cancer cells via β-catenin and p53.
Highlights
We previously reported that overexpression of Axin downregulates T cell factor-4 (TCF-4) transcription
We found that LiCl treatment inhibited the downregulation of TCF-4 promoter activity and TCFmediated gene transcription in Axin, AxinΔb-ca and AxinΔp53 expressing A549 cells (P > 0.05, Figure 6E and 6F)
We treated A549 by LiCl to block the degradation of b-catenin, we found that in A549 cells after LiCl treatment, the expression levels of b-catenin and TCF-4 as well as the TCF-4 promoter and TCF-mediated gene transcription activity were significantly higher than those in nontreated cells, but this did not happen in BE1 cells
Summary
We previously reported that overexpression of Axin downregulates T cell factor-4 (TCF-4) transcription. The wingless/int (Wnt) signaling pathway plays an important role in tumor cell de-differentiation and proliferation [1]. Activation of the Wnt pathway requires nuclear accumulation of b-catenin, as well as association of b-catenin and T cell factor-4 (TCF-4). The Axin antagonist, Dishevelled, positively regulates the Wnt signaling pathway by binding to Axin directly [10,11], and prevents inhibition of GSK-3b-dependent phosphorylation of bcatenin. Most likely this occurs through dissociation of the APC/Axin/GSK-3b complex [11,12]
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