Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner

Tamura, Masahito; Tanaka, Shinji; Fujii, Tomoaki; Aoki, Aya; Komiyama, Hiromitu; Ezawa, Kiyoshi; Sumiyama, Kenta; Sagai, Tomoko; Shiroishi, Toshihiko

doi:10.1016/j.ygeno.2007.01.003

Cited by 268 publications

(244 citation statements)

References 32 publications

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“…Although the two families evolved from a common ancestor, phylogenetic analysis has indicated that the two clades are distinct, 24 leaving DFNA5 with only a single closely related protein: PJVK. The first part of PJVK shows high similarity with DFNA5, but does not induce apoptosis.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Although it has been demonstrated that these genes are expressed in the intestinal epithelium, the function of this subfamily is relatively uncharacterized (Tamura et al, 2007).…”

Section: Characterization Of Nkx22mentioning

confidence: 99%

Lmx1a functions in intestinal serotonin-producing enterochromaffin cells downstream of Nkx2.2

et al. 2016

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Intestinal hormone-producing cells represent the largest endocrine system in the body, but remarkably little is known about enteroendocrine cell type specification in the embryo and adult. We analyzed stage-and cell type-specific deletions of Nkx2.2 and its functional domains in order to characterize its role in the development and maintenance of enteroendocrine cell lineages in the mouse duodenum and colon. Although Nkx2.2 regulates enteroendocrine cell specification in the duodenum at all stages examined, it controls the differentiation of progressively fewer enteroendocrine cell populations when deleted from Ngn3 + progenitor cells or in the adult duodenum. During embryonic development Nkx2.2 regulates all enteroendocrine cell types, except gastrin and preproglucagon. In developing Ngn3+ enteroendocrine progenitor cells, Nkx2.2 is not required for the specification of neuropeptide Y and vasoactive intestinal polypeptide, indicating that a subset of these cell populations derive from an Nkx2.2-independent lineage. In adult duodenum, Nkx2.2 becomes dispensable for cholecystokinin and secretin production. In all stages and Nkx2.2 mutant conditions, serotonin-producing enterochromaffin cells were the most severely reduced enteroendocrine lineage in the duodenum and colon. We determined that the transcription factor Lmx1a is expressed in enterochromaffin cells and functions downstream of Nkx2.2. Lmx1a-deficient mice have reduced expression of Tph1, the rate-limiting enzyme for serotonin biosynthesis. These data clarify the function of Nkx2.2 in the specification and homeostatic maintenance of enteroendocrine populations, and identify Lmx1a as a novel enterochromaffin cell marker that is also essential for the production of the serotonin biosynthetic enzyme Tph1.

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“…GSDMB (also known as GSDML) is a novel protein that belongs to the gasdermin (GSDM) family that consists of four human genes: GSDMA, GSDMB, GSDMC and GSDMD [17]. A mouse or rat ortholog of the GSDMB gene has not been identified, and it may have evolved independently in humans through a GSDM gene duplication [18].…”

Section: Resultsmentioning

confidence: 99%

“…The human GSDMB gene consists of 12 exons and four different splice variants have been described, which differ in exons 6 and 7 of the GSDMB gene [19]. GSDMB has been linked to cancer progression and is expressed in human gastric, liver, colon and breast cancer cell lines and carcinomas [17,19]. Although several genetic studies show a strong association of GSDMB with asthma, no functional studies to date have investigated the biological role of GSDMB in asthma and related airway cell types.…”

Section: Resultsmentioning

confidence: 99%

Why is Chromosome 17q21 linked to Asthma?

Das¹,

Broide²

2016

Insights Allergy Asthma Bronchitis

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Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner

Cited by 268 publications

References 32 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

Lmx1a functions in intestinal serotonin-producing enterochromaffin cells downstream of Nkx2.2

Why is Chromosome 17q21 linked to Asthma?

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