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.
Highlights
Four and a Half LIM protein 2 (FHL2) is known to function as an adaptor protein that is able to transactivate gene expression
Among the five transcript variants of FHL2, exon 1a is only found in transcript variant 4, which followed by the coding sequence from exon 4 to 8
Results showed that activities of all FHL2 1a mutants are similar while 1b promoter presented the highest activity at the deletion to 2138
Summary
Four and a Half LIM protein 2 (FHL2) is known to function as an adaptor protein that is able to transactivate gene expression. It is predominantly expressed in the human heart tissue, its expression in a wide range of normal human tissues has been well documented [1,2,3,4]. Concerning the transcriptional regulation of FHL2, the human FHL2 gene expresses five transcript variants and all of them translate into the same FHL2 protein [19] Among these variants, there are two alternative 59 exons, namely exon 1a in transcript variant 4 and exon 1b in transcript variants 1, 2, 3 and 5. The 1b promoter, the upstream promoter of exon 1b, has been previously characterized [19]
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