The deafness gene GSDME: its involvement in cell apoptosis, secondary necrosis, and cancers

Li, Yue-Qi; Peng, Junwen; Peng, Jun; Luo, Xiu-Ju

doi:10.1007/s00210-019-01674-7

Cited by 26 publications

(23 citation statements)

References 46 publications

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“…Gasdermin proteins play complex and sometimes opposed roles in cancer [6][7][8][9][19][20][21]. While GSDME and GSDMA are broadly considered as tumor suppressor genes the implication of the other GSDMs in malignancy is less clear [6][7][8][9][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

“…Under certain stimuli and circumstances, the NT is exposed or released, mostly via specific protease cleavage and produces cell damage generally through the formation of NT membrane pores [12-16], among other potential mechanisms [10, 17, 18]. In the recent years, these GSDM pro-cell death activities have been proposed to play a role in the pathogenesis of multiple diseases (inflammatory, infectious, neurological, among others [3-5]) and also in the progression and clinical behavior of cancer [6-9, 19]. In this sense, due to their potential cytotoxic function, GSDME and GSDMA are generally silenced in cancers and broadly considered as potential tumor suppressor genes [7, 9, 19-21], while GSDMC and GSDMD have been associated to pro- and anti-tumor effects, depending on the context [22-26].…”

Section: Introductionmentioning

confidence: 99%

“…In the recent years, these GSDM pro-cell death activities have been proposed to play a role in the pathogenesis of multiple diseases (inflammatory, infectious, neurological, among others [3-5]) and also in the progression and clinical behavior of cancer [6-9, 19]. In this sense, due to their potential cytotoxic function, GSDME and GSDMA are generally silenced in cancers and broadly considered as potential tumor suppressor genes [7, 9, 19-21], while GSDMC and GSDMD have been associated to pro- and anti-tumor effects, depending on the context [22-26]. Strikingly, GSDMB is frequently over-expressed in the cytoplasm (and/or the nucleus) of esophageal, gastric, colon, liver and breast tumor cells, as well as cervical and head and neck squamous cell carcinomas [27-33].…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Analysis of the Role of Gasdermin-B (Gsdmb) in Cancer Using Novel Knock-in Mouse Models

Sarrió

Rojo-Sebastián

Teijo

et al. 2021

Preprint

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Background: Gasdermin-B gene (GSDMB) is frequently over-expressed in tumors, and its shortest translated variant (isoform 2; GSDMB2) increases aggressive behavior in breast cancer cells. Paradoxically, GSDMB could have either pro-tumor or tumor suppressor properties depending on the biological context. Since GSDMB gene is not present in the mouse genome, deciphering fully the functional roles of GSDMB in cancer requires novel in vivo models. Methods: We first generated by gene targeting a conditional knock-in mouse model (R26-STOP-GB2) harboring human GSDMB2 transcript within the ROSA26 locus. We next derived the R26-GB2 model ubiquitously expressing GSDMB2 in multiple tissues (confirmed by western blot and immunohistochemistry) and performed a comprehensive histopathological analysis in multiple tissues from 75 male and female mice up to 18 months of age. Additionally, we produced the double transgenic model R26-GB2/MMTV-PyMT, co-expressing GSDMB2 and the Polyoma-Middle-T oncogene, and assessed breast cancer generation and progression in GSDMB2-homozygous (n=10) and control (n=17) female mice up to 15 weeks of age. Results: In the R26-GB2 model, which showed different GSDMB2 cytoplasmic and/or nuclear localization among tissues, we investigated if GSDMB2 expression had intrinsic tumorigenic activity. 41% of mice developed spontaneous lung tumors, but neither the frequency nor the histology of these neoplasias was significantly different from wildtype animals. Strikingly, while 17% control mice developed gastric carcinomas, no GSDMB2-positive mice did. No other tumor types or additional histological alterations were frequently seen in these mice. In the R26-GB2/MMTV-PyMT model, the strong nucleus-cytoplasmic GSDMB2 expression in breast cancer cells did not significantly affect cancer formation (number of tumors, latency, tumor weight, histology or proliferation) or lung metastasis potential compared to controls. Conclusions: GSDMB2 expression alone does not have an overall tumorigenic potential in mice, but it might reduce gastric carcinogenesis. Contrary to human cancers, GSDMB2 upregulation does not significantly affect breast cancer generation and progression in mouse models. However, to evidence the GSDMB functions in cancer and other pathologies in vivo may require the presence of specific stimulus or cellular contexts. Our novel mouse strains will serve as the basis for the future development of more precise tissue-specific and context-dependent cancer models.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In Vivo Analysis of the Role of Gasdermin-B (Gsdmb) in Cancer Using Novel Knock-in Mouse Models

Sarrió

Rojo-Sebastián

Teijo

et al. 2021

Preprint

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“…Most deafness-causing mutations in GSDME lead to deletion of GSDME C-terminal transcription and could induce spontaneous pyroptosis [30].In addition to hearing loss, GSDME has been linked to many cancers, such as breast [31,32], epatocellular [33], gastric [34] colorectal [35]cancers. In these cancers, GSDME methylation was signi cantly increased, resulting in GSDME epigenetic silencing, which reduced GSDME levels [36].GSDME can be regulated by p53 because the presence of p53 binding sites in GSDME intron 1 [36].Treatment with the demethylating agent, such as 5-aza-2'-deoxycytidine, can restore p53-induced GSDME expression [37]. Based on these reports, GSDME is considered to be a tumor suppressor gene because inactivation of GSDME inhibits its necrotic function, thus promoting tumor formation.…”

Section: Discussionmentioning

confidence: 99%

Alleviation of Disease Activity in Lupus mice by Blocking Secondary Pyroptosis of Renal Tubular Epithelial Cells

Luo

Yang

Zhai

et al. 2021

Preprint

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Background:Increased apoptosis and/or defect in clearance apoptotic cells resulting in massive secondary necrosis have been recognized as the main causes of systemic lupus erythematosus. Recent findings have revealed that GSDME, a membrane pore protein downstream of caspase-3, is a key mediator of secondary pyroptosis and cellular membrane disruption. Here, we aim to investigate the effects of secondary pyroptosis on disease activity in lupus mice. Methods:In vivo, Pristane-induced lupus mice were treated with JNK inhibitor SP600125 or vehicle. The disease severity was evaluated and the expression of GSDME and cleaved-caspase-3 detected. In vitro, HK2 human tubular epithelial cells were pretreated with SP600125, followed by treatment with apoptosis inducer, TNF+CHX, or SLE sera. And then the secondary pyroptosis were examined. Results:In vivo, high levels of GSDME expression were revealed in renal tubules in PIL mice and SLE patients. In lupus mice, SP600125 administration effectively ameliorated lupus-like features and importantly, reduced the expression of GSDME and cleaved caspase-3 in renal tubules. In vitro, treatment with TNF+CHX or SLE sera induced HK2 cells to undergo secondary pyroptosis in a caspase-3-GSDME dependent manner. Likewise, SP600125 significantly reduced GSDME expression and decreased the secondary pyroptosis in HK2 cells. Conclusions:The GSDME-mediated pyroptosis may be one of the pathogenesis of SLE and targeting GSDME may be a potential strategy for treating SLE.

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“…Skipping of exon 8 at the mRNA level leads to premature termination of the encoded protein, which results in cochlear hair cell loss via apoptosis ( Rogers et al, 2017 ). The DFNA5 protein has an N-terminal domain, with apoptosis-inducing activity, and a C-terminal domain, which folds back to shield the N-terminus and prevent inappropriate initiation of apoptosis ( Li et al, 2019 ). Skipping of exon 8 in DFNA5 transcripts results in the translation of a truncated protein with apoptosis-inducing activity, owing to the loss of the protective C-terminal domain.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Novel Heterozygous DFNA5 Splicing Variant Responsible for Autosomal Dominant Non-syndromic Hearing Loss in a Chinese Family

Chen

Jia

et al. 2020

Front. Genet.

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Autosomal dominant non-syndromic hearing loss (ADNSHL) has a broad phenotypic spectrum which includes bilateral, symmetrical, and high-frequency sensorineural hearing loss, that eventually progresses into hearing loss at all frequencies. Several genetic variations have been identified as causal factors underlying deafness, autosomal dominant 5 (DFNA5) gene-related hearing loss. Here, we report a novel mutation (c.991-1G > C) in DFNA5, which co-segregated with late-onset ADNSHL in a Chinese family and was identified via exome sequencing and Sanger sequencing of DNA from peripheral blood of the family members. Further sequencing of cDNA derived from peripheral blood mRNA revealed that the c.991-1G >C mutation led to the skipping of exon 8, which is a known pathogenic mechanism for DFNA5-related hearing loss.

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The deafness gene GSDME: its involvement in cell apoptosis, secondary necrosis, and cancers

Cited by 26 publications

References 46 publications

In Vivo Analysis of the Role of Gasdermin-B (Gsdmb) in Cancer Using Novel Knock-in Mouse Models

In Vivo Analysis of the Role of Gasdermin-B (Gsdmb) in Cancer Using Novel Knock-in Mouse Models

Alleviation of Disease Activity in Lupus mice by Blocking Secondary Pyroptosis of Renal Tubular Epithelial Cells

Case Report: Novel Heterozygous DFNA5 Splicing Variant Responsible for Autosomal Dominant Non-syndromic Hearing Loss in a Chinese Family

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