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A serine in exon 11 determines the full transcriptional activity of TCF-4 in lung carcinoma cells

Author:
Yang, Bijun, Xu, Yu, Wang, Xiaohui, Liu, Yuliang
Source:
Biochemical and biophysical research communications 2019 v.508 no.3 pp. 675-681
ISSN:
0006-291X
Subject:
T-lymphocytes, antineoplastic activity, binding sites, enzyme activity, epithelial cells, exons, gene expression, in vivo studies, luciferase, lung neoplasms, lungs, messenger RNA, mutation, neoplasm cells, prognosis, reverse transcriptase polymerase chain reaction, serine, transcription (genetics)
Abstract:
Activation of T cell factor-4 (TCF-4) is causally linked to the development of lung carcinoma, while the mechanism of sequence-dependent TCF-4 activity is still obscure. Using reverse transcription-polymerase chain reaction (RT-PCR), here, we demonstrated that sequences of exon 11 in TCF-4 were present in lung carcinoma cells but not in normal lung epithelial cells. Loss of exon 11 in TCF-4 inhibited TCF-4-induced cell growth of lung carcinoma and prolonged the survival time of Lewis lung carcinoma (LLC) tumor-bearing mice. Mechanistically, loss of exon 11 in TCF-4 attenuated the binding activity between TCF-4 protein and its canonical binding site, inhibited TOP/FOP luciferase activity and suppressed mRNA expression of Wnt signaling targets. By performing truncated and site-directed mutations, we further demonstrated that the 16th amino acid serine in exon 11 was responsible for TCF-4-mediated Wnt signaling. In vivo experiments indicated that a mutation of the 16th amino acid serine in exon 11 of TCF-4 could mimic the anti-tumor effect of Wnt signaling inhibitor. Taken together, we identified a serine determining the transcriptional activity of TCF-4 in lung carcinoma cells, and sequencing of TCF-4 mRNA might be an effective strategy to evaluate the Wnt pathway activation and prognosis in lung cancer.
Agid:
6250486