Differential expression and localisation of gasdermin-like (GSDML), a novel member of the cancer-associated GSDMDC protein family, in neoplastic and non-neoplastic gastric, hepatic, and colon tissues

Carl-McGrath, Stacy; Schneider‐Stock, Regine; Ebert, Matthias; Röcken, Christoph

doi:10.1080/00313020701716250

Cited by 78 publications

(82 citation statements)

References 24 publications

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“…2), as reported by Carl-McGrath et al (2008). We detected a single major band in normal tissues with weak GSDMB expression, and sequencing revealed that this band represents the full-length GSDMB transcript.…”

Section: Resultssupporting

confidence: 83%

“…These findings suggest that over-expression and ectopic expression of the full-length GSDMB transcript has no effect on cancer development and progression. Given these results, it is notable that GSDMB has several splicing variants (Carl-McGrath et al, 2008) and that some of these transcripts lack the conserved C-terminus of the GSDMB protein . In mice, one of the most severe skin phenotypes is observed in the Gsdma3 mutant allele Gsdma3 Dfl , in which a B2-element insertion results in the production of a truncated Gsdma3 protein (Lunny et al, 2005) similar to the truncated GSDMB protein observed in human gastric cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it was recently reported that GSDMA is involved in the TGF-beta signaling that mediates apoptosis in the gastric epithelium (Saeki et al, 2007). In contrast, GSDMB is expressed in human cancer tissues, including gastric, hepatic, colon, uterine, and cervical cancers, and cancer-derived cell lines (Carl-McGrath et al, 2008;Sun et al, 2008). Although GSDMA and GSDMB belong to the same gene family and are located near to each other on 17q21, expression of GSDMA and GSDMB during cancer development and progression are non-overlapping and complementary.…”

Section: Introductionmentioning

confidence: 99%

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Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB)

et al. 2010

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GASDERMIN B (GSDMB) belongs to the novel gene family GASDERMIN (GSDM). All GSDM family members are located in amplicons, genomic regions often amplified during cancer development. Given that GSDMB is highly expressed in cancerous cells and the locus resides in an amplicon, GSDMB may be involved in cancer development and/or progression. However, only limited information is available on GSDMB expression in tissues, normal and cancerous, from cancer patients. Furthermore, the molecular mechanisms that regulate GSDMB expression in gastric tissues are poorly understood. We investigated the spatiotemporal expression patterns of GSDMB in gastric cancer patients and the 5' regulatory sequences upstream of GSDMB. GSDMB was not expressed in the majority of normal gastric-tissue samples, and the expression level was very low in the few normal samples with GSDMB expression. Most pre-cancer samples showed moderate GSDMB expression, and most cancerous samples showed augmented GSDMB expression. Analysis of genome sequences revealed that an Alu element resides in the 5' region upstream of GSDMB. Reporter assays using intact, deleted, and mutated Alu elements clearly showed that this Alu element positively regulates GSDMB expression and that a putative IKZF binding motif in this element is crucial to upregulate GSDMB expression.

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Section: Resultssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB)

et al. 2010

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“…Gsdma3 expression was observed mainly in the hair follicles (Runkel et al, 2004;Lunny et al, 2005). In addition to the stomach, expression of GSDMB (GSDML) was also reported in the colon and liver (Carl-McGrath et al, 2008), which has no mouse corresponding gene. In the mouse gastrointestinal tract, expression of Gsdmc and Gsdmd was observed mainly in the colon and small intestine, respectively ; however, a GSDMC (MLZE) transcript was detected by Northern blot analysis exclusively in the trachea and spleen, not in the gastrointestinal tract (Watabe et al, 2001).…”

Section: Discussionmentioning

confidence: 95%

Distinctive expression and function of four GSDM family genes (GSDMA‐D) in normal and malignant upper gastrointestinal epithelium

Saeki¹,

Usui²,

Aoyagi³

et al. 2008

Genes Chromosomes & Cancer

232

224

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Gasdermin (GSDM or GSDMA), expressed in the upper gastrointestinal tract but frequently silenced in gastric cancers (GCs), regulates apoptosis of the gastric epithelium. It has three human homologs, GSDMB, GSDMC, and GSDMD (GSDM family) and they are considered to be involved in the regulation of epithelial apoptosis but not yet known. We investigated the expression pattern of the family genes in the upper gastrointestinal epithelium and cancers. Reverse transcriptase-polymerase chain reaction revealed that, unlike GSDMA expressed in differentiated cells, GSDMB is expressed in proliferating cells and GSDMD in differentiating cells. GSDMC, meanwhile, is expressed in both differentiating and differentiated cells. Colony formation assay showed that GSDMB, closely related to GSDMA, has no cell-growth inhibition activity in gastric cancer cells, and that GSDMC and GSDMD, respectively, exhibit the activity with different strengths from that of GSDMA. Expression analyses of the four family genes in esophageal and GCs suggested that GSDMC and GSDMD as well as GSDMA are tumor suppressors and that GSDMB, which was amplified and overexpressed in some GCs, could be an oncogene. The results of the expression analysis and colony formation assay suggest that each family gene may have a distinct function in the upper gastrointestinal epithelium.

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“…T he human genome encodes four gasdermin (GSDM) proteins (GSDMA to -D) that are expressed in epithelial cells and have regulatory functions in normal cell proliferation and differentiation and the maintenance of the epithelial cell barrier (1,2). The mouse genome contains three clusters of GSDM genes, encoding eight GSDMs (Gsdma1 to -3, Gsdmc1 to -4, and Gsdmd), but lacks the analog of the human GSDMB (also known as GSDML or PRO2521) (1).…”

mentioning

confidence: 99%

Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein

Chao

Kulakova

Herzberg

2017

Proc. Natl. Acad. Sci. U.S.A.

150

189

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The exact function of human gasdermin-B (GSDMB), which regulates differentiation and growth of epithelial cells, is yet to be elucidated. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, GSDMB gene amplification and protein overexpression indicate a poor response to HER2-targeted therapy. Genome-wide association studies revealed a correlation between GSDMB SNPs and an increased susceptibility to Crohn's disease, ulcerative colitis, and asthma. The N-and C-terminal domains of all gasdermins possess lipid-binding and regulatory activities, respectively. Inflammatory caspases cleave gasdermin-D in the interdomain linker but not GSDMB. The cleaved N-terminal domain binds phosphoinositides and cardiolipin, forms membrane-disrupting pores, and executes pyroptosis. We show that both full-length GSDMB and the N-terminal domain bind to nitrocellulose membranes immobilized with phosphoinositides or sulfatide, but not with cardiolipin. In addition, the GSDMB N-terminal domain binds liposomes containing sulfatide. The crystal structure of the GSDMB C-terminal domain reveals the structural impact of the amino acids encoded by SNPs that are linked to asthma and inflammatory bowel disease (IBD). A loop that carries the polymorphism amino acids corresponding to healthy individuals (Gly299:Pro306) exhibits high conformational flexibility, whereas the loop carrying amino acids found in individuals with increased disease risk (Arg299:Ser306) exhibits a well-defined conformation and higher positive surface charge. Apoptotic executioner caspase-3, -6, and -7, but not the inflammatory caspases, cleave GSDMB at 88 DNVD 91 within the N-terminal domain. Selective sulfatide binding may indicate possible function for GSDMB in the cellular sulfatide transport.GSDMB | X-ray crystallography | disease risk polymorphism | complex trait inflammatory disease | lipid binding

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Differential expression and localisation of gasdermin-like (GSDML), a novel member of the cancer-associated GSDMDC protein family, in neoplastic and non-neoplastic gastric, hepatic, and colon tissues

Cited by 78 publications

References 24 publications

Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB)

Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB)

Distinctive expression and function of four GSDM family genes (GSDMA‐D) in normal and malignant upper gastrointestinal epithelium

Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein

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