Characterization of a gene that is inversely correlated with estrogen receptor expression (ICERE‐1) in breast carcinomas

Thompson, Devon A.; Weigel, Ronald J.

doi:10.1046/j.1432-1327.1998.2520169.x

Cited by 67 publications

(65 citation statements)

References 4 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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DFNA5 was first identified as a gene causing autosomal dominant hearing loss (HL). Different mutations have been found, all exerting a highly specific gain-of-function effect, in which skipping of exon 8 causes the HL. Later reports revealed the involvement of the gene in different types of cancer. Epigenetic silencing of DFNA5 in a large percentage of gastric, colorectal and breast tumors and p53-dependent transcriptional activity have been reported, concluding that DFNA5 acts as a tumor suppressor gene in different frequent types of cancer. Despite these data, the molecular function of DFNA5 has not been investigated properly. Previous transfection studies with mutant DFNA5 in yeast and in mammalian cells showed a toxic effect of the mutant protein, which was not seen after transfection of the wild-type protein. Here, we demonstrate that DFNA5 is composed of two domains, separated by a hinge region. The first region induces apoptosis when transfected in HEK293T cells, the second region masks and probably regulates this apoptosis inducing capability. Moreover, the involvement of DFNA5 in apoptosis-related pathways in a physiological setting was demonstrated through gene expression microarray analysis using Dfna5 knockout mice. In view of its important role in carcinogenesis, this finding is expected to lead to new insights on the role of apoptosis in many types of cancer. In addition, it provides a new line of evidence supporting an important role for apoptosis in monogenic and complex forms of HL. Keywords: tumor suppressor; hearing loss; apoptosis; dfna5; cancer; GSEA INTRODUCTION DFNA5 first was discovered in a Dutch family with autosomal dominant hearing loss (HL). 1 Not much was known concerning its cellular function and how its function was related to HL. Recently, a novel mutation in DFNA5 has been identified in a Korean family, totaling five families with DFNA5 HL. 2 These families all have different genomic DFNA5 mutations, but in each case the DFNA5 mRNA transcript skips exon 8, resulting in a frameshift and a premature truncation of the protein. [1][2][3][4][5] These findings have led to the hypothesis that DFNA5-associated HL is attributable to a highly specific gain-of-function mutation, in which skipping of one exon causes disease while mutations in other parts of this gene may not result in HL at all. Further experimental evidence for this hypothesis was provided by the finding that transfection of mutant DFNA5 causes cell death in both yeast 6 and mammalian 7 cells and by the discovery of a new DFNA5 mutation. 8 The latter mutation truncated the protein in the fifth exon, but did not segregate with HL and was present in family members with normal hearing. The hypothesis was further corroborated by a mouse that lacked the Dfna5 protein. This knockout (KO) mouse did not display any HL and, as a consequence, was not a suitable animal model to study DFNA5-associated HL. 9 To date, little information is available on the physiological function of DFNA5. However, since its identification, the small num...

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Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…An intronic insertion and/or mutation leads to premature termination of the protein, resulting in a nonsyndromic progressive hearing loss (Van Laer et al, 1998). DFNA5 was also designated ICERE-1 (inversely correlated with estrogen receptor expression) due to its lower expression in estrogen receptor (ER)-positive breast cancers compared to ER-negative tumors (Thompson and Weigel, 1998). In addition, etoposide resistance in melanoma cells is associated with decreased DFNA5 expression (Lage et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma

et al. 2008

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To identify novel methylated gene promoters, we compared differential RNA expression profiles of colorectal cancer (CRC) cell lines with or without treatment of 5-aza-2 0 -deoxycytidine (5-aza-dC). Out of 1776 genes that were initially 'absent (that is, silenced)' by gene expression array analysis, we selected 163 genes that were increased after 5-aza-dC treatment in at least two of three CRC cell lines. The microarray results were confirmed by Reverse Transcription-PCR, and CpG island of the gene promoters were amplified and sequenced for examination of cancer-specific methylation. Among the genes identified, the deafness, autosomal dominant 5 gene, DFNA5, promoter was found to be methylated in primary tumor tissues with high frequency (65%, 65/100). Quantitative methylation-specific PCR of DFNA5 clearly discriminated primary CRC tissues from normal colon tissues (3%, 3/100). The mRNA expression of DFNA5 in four of five colon cancer tissues was significantly downregulated as compared to normal tissues. Moreover, forced expression of full-length DFNA5 in CRC cell lines markedly decreased the cell growth and colony-forming ability whereas knockdown of DFNA5 increased cell growth in culture. Our data implicate DFNA5 as a novel tumor suppressor gene in CRC and a valuable molecular marker for human cancer.

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“…The DFNA5 gene was initially identified as one of the genes whose expression is inversely correlated with that of the estrogen receptor in breast carcinomas, and therefore, it was initially designated as ICERE-1 (inversely correlated with estrogen receptor expression) (Thompson and Weigel 1998). However, later on, a mutation in the DFNA5 gene was reported to be associated with autosomal-dominant, nonsyndromic hearing impairment in an extended Dutch family (Van Laer et al 1998).…”

Section: Introductionmentioning

confidence: 99%

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

Masuda

Futamura²,

Kamino³

et al. 2006

J Hum Genet

104

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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.

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Characterization of a gene that is inversely correlated with estrogen receptor expression (ICERE‐1) in breast carcinomas

Cited by 67 publications

References 4 publications

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

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

Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma

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

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