The potential role of DFNA5, a hearing impairment gene, in p53-mediated cellular response to DNA damage

Abstract

The tumor suppressor p53 plays a crucial role in the cellular response to DNA damage by transcriptional activation of numerous downstream genes. Although a considerable number of p53 target genes have been reported, the precise mechanism of p53-regulated tumor suppression still remains to be elucidated. Here, we report a novel role of the DFNA5 gene in p53-mediated etoposide-induced cell death. The DFNA5 gene has been previously reported to be responsible for autosomal-dominant, nonsyndromic hearing impairment. The expression of the DFNA5 gene was strongly induced by exogenous and endogenous p53. The chromatin immunoprecipitation assay indicated that a potential p53-binding sequence is located in intron 1 of the DFNA5 gene. Furthermore, the reporter gene assay revealed that the sequence displays p53-dependent transcriptional activity. The ectopic expression of DFNA5 enhanced etoposide-induced cell death in the presence of p53; however, it was inhibited in the absence of p53. Finally, the expression of DFNA5 mRNA was remarkably induced by gammaray irradiation in the colon of p53(+/+) mice but not in that of p53(-/-) mice. These results suggest that DFNA5 plays a role in the p53-regulated cellular response to genotoxic stress probably by cooperating with p53.

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

“…However, since its identification, the small number of papers published on DFNA5 almost all point to a possible involvement in cancer biology. [10][11][12][13][14][15][16] Especially during the last 3 years, DFNA5 emerged from several genomic screens identifying new tumor suppressor genes. Further analysis showed that the DFNA5 gene is epigenetically inactivated in several types of cancer, including gastric, colorectal and breast cancer.…”

“…15 These recent data also explain earlier findings that were not well understood at the time, such as the increased resistance to the chemotherapeutic reagent etoposide in melanoma cells with decreased transcription of DFNA5, 11 or the finding that DFNA5 is induced by p53 through a p53-binding site located in intron 1. 12 Webb et al 17 demonstrated that DFNA5 mRNA expression increased after treatment of human acute lymphoblastic leukemia cell lines with the glucocorticoid dexamethasone. This increase was only found in cells that underwent apoptosis in response to glucocorticoid treatment.…”

Regulation of apoptosis by p53-inducible transmembrane protein containing sushi domain

“…We established the p53-knock down (p53-KD) and the control (Cont) cell lines as described previously (3)(4)(5)(6). Briefly, HepG2, LS174T, HCT116 and LC176 cells were infected with SI-MSCV-puro-H1R-p53Ri retrovirus for down-regulation of p53 expression and with SI-MSCV-puro-H1R-control retrovirus for negative control.…”

“…To identify additional transcriptional targets of p53 in the human genome, we used cDNA microarrays and screened p53-inducible transcripts according to previously described methods (3,5). In these experiments, p21/waf1, whose expression was clearly induced by p53, was used as the positive control; the results indicated that p53 upregulated the expression of approximately 100 genes.…”

“…Brain-specific angiogenesis inhibitor 1 (BAI1) and thrombospondin 1 (TSP1) suppress angiogenesis and inhibit tumor growth. In our previous studies, we have isolated and characterized additional p53 target genes by using cDNA microarray technology, and we have reported the p53-dependent transcription of genes encoding deafness, autosomal dominant 5 (DFNA5), Semaphorin 3F (SEMA3F), B cell linker protein (BLNK), and unc-5 homolog A (UNC5A) (3)(4)(5)(6). More studies on these target genes would clarify the physiological function of p53 as a tumor suppressor gene.…”