title: Transcriptional regulation of the tumor suppressor FHL2 by p53 in human kidney and liver cells.
abstract: Four and a Half LIM protein 2 (FHL2) is a LIM domain only protein that is able to form various protein complexes and regulate gene transcription. Recent findings showed that FHL2 is a potential tumor suppressor gene that was down-regulated in hepatocellular carcinoma (HCC). Moreover, FHL2 can bind to and activate the TP53 promoter in hepatic cells. In this study, the activity of the two promoters of FHL2, 1a and 1b, were determined in the human embryonic kidney cell line HEK293 and the activation of these two promoters by p53 was investigated. Our results showed that the 1b promoter has a higher activity than the 1a promoter in HEK 293 cells but the 1a promoter is more responsive to the activation by p53 when compared with the 1b promoter. The regulation of FHL2 by p53 was further confirmed in liver cells by the overexpression of p53 in Hep3B cells and the knockdown of p53 in HepG2 cells. Combining promoter activity results of truncated mutants and predictions by bioinformatics tools, a putative p53 binding site was found in the exon 1a of FHL2 from +213 to +232. The binding between the p53 protein and the putative p53 binding site was then validated by the ChIP assay. Furthermore, the expression of FHL2 and TP53 were down-regulated in majority of HCC tumour samples (n = 41) and significantly correlated (P = 0.026). Finally, we found that the somatic mutation 747 (G→T), a hot spot mutation of the TP53 gene, is potentially associated with a higher expression of FHL2 in HCC tumour samples. Taken together, this is the first in-depth study about the transcriptional regulation of FHL2 by p53.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Junwei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Man-Shan
authors.initials: MS
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Chor-Fung
authors.initials: CF
authors.lastname: Ng
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Yuen-Keng
authors.initials: YK
authors.lastname: Ng
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Paul Bo-San
authors.initials: PB
authors.lastname: Lai
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Stephen Kwok-Wing
authors.initials: SK
authors.lastname: Tsui
mesh_terms: D000818:Animals; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53