Amelotin gene expression is temporarily being upregulated at the initiation of apoptosis induced by TGFβ1 in mouse gingival epithelial cells

Nakayama, Yohei; Matsui, Sari; Nöda, Keisuke; Yamazaki, Mizuho; Iwai, Yasunobu; Matsumura, Hideki; Izawa, Takashi; Tanaka, Eiji; Ganß, Bernhard; Ogata, Yorimasa

doi:10.1007/s10495-016-1279-5

Cited by 13 publications

(30 citation statements)

References 47 publications

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“…IL‐1β production is initiated at early stage of inflammation and plays a prominent role in the pathogenesis of periodontitis , and the concentration is increased in the periodontium . We have shown that AMTN gene expression is temporarily increased at the initiation of apoptosis by TGF‐β1 . TNF‐α stimulates human AMTN gene transcription in gingival epithelial cells .…”

Section: Discussionmentioning

confidence: 82%

Transcriptional regulation of human amelotin gene by interleukin‐1β

et al. 2018

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One of the major causes of tooth loss is chronic inflammation of the periodontium, the tissues surrounding the tooth. Amelotin ( AMTN ) is a tooth enamel protein which is expressed in maturation‐stage ameloblasts and also in the internal basal lamina of junctional epithelium, a unique epithelial structure attached to the tooth surface which protects against the constant microbiological challenge to the periodontium. Localization of AMTN suggests that its function could be involved in the dentogingival attachment. The purpose of this study was to investigate the effect of interleukin‐1β ( IL ‐1β) on AMTN gene transcription in human gingival epithelial Ca9‐22 cells. IL ‐1β increased AMTN mRNA and protein levels at 3 h, and the levels reached maximum at 6 and 12 h. IL ‐1β induced luciferase activities of human AMTN gene promoter constructs (−211, −353, −501, −769, and −950AMTN), but these activities were partially inhibited in −353AMTN constructs that included 3‐bp mutations in CCAAT /enhancer binding protein 1 (C/ EBP 1), C/ EBP 2, and Ying Yang 1 ( YY 1) elements. Transcriptional activities induced by IL ‐1β were abrogated by protein kinase A ( PKA ), tyrosine kinase, mitogen‐activated protein kinase kinase ( MEK 1/2), and phosphatidylinositol 3‐kinase ( PI 3K) inhibitors. Gel shift and ChIP assays showed that IL ‐1β increased C/ EBP β binding to C/ EBP 1 and C/ EBP 2, and YY 1 binding to YY 1 elements after 3 h, and that these DNA –protein interactions were inhibited by PKA , tyrosine kinase, MEK 1/2, and PI 3K inhibitors. These results demonstrated that IL ‐1β increases AMTN gene transcription in human gingival epithelial cells mediated through C/ EBP 1, C/ EBP 2, and YY 1 elements in the human AMTN gene promoter.

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Section: Discussionmentioning

confidence: 82%

Transcriptional regulation of human amelotin gene by interleukin‐1β

et al. 2018

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“…In the previous study, we reported that the AMTN expressions were temporally induced by TGFβ1 (10 ng/ml) for 24 and 48 hr (Nakayama et al, , ). Results of immunofluorescence showed that the AMTN expressions were increased by TGFβ1 at 24 hr (Figure e) and then decreased at 72 hr (Figure i).…”

Section: Resultsmentioning

confidence: 92%

Negative feedback by SNAI2 regulates TGFβ1‐induced amelotin gene transcription in epithelial–mesenchymal transition

Nakayama

Tsuruya

Nöda

et al. 2018

Journal Cellular Physiology

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Junctional epithelium (JE) demonstrates biological responses with the rapid turnover of gingival epithelial cells. The state occurs in inflammation of gingiva and wound healing after periodontal therapy. To understand the underlying mechanisms and to maintain homeostasis of JE, it is important to investigate roles of JE‐specific genes. Amelotin (AMTN) is localized at JE and regulated by inflammatory cytokines and apoptotic factors that represent a critical role of AMTN in stabilizing the dentogingival attachment, which is an entrance of oral bacteria. In this study, we demonstrated that the AMTN gene expression was regulated by SNAI2 and transforming growth factor β1 (TGFβ1)‐induced epithelial–mesenchymal transition (EMT) that occurs in wound healing and fibrosis during chronic inflammation. SNAI2 downregulated AMTN gene expression via SNAI2 bindings to E‐boxes (E2 and E4) in the mouse AMTN gene promoter in EMT of gingival epithelial cells. Meanwhile, TGFβ1‐induced AMTN gene expression was attenuated by SNAI2 and TGFβ1‐induced SNAI2, without inhibition of the TGFβ1‐Smad3 signaling pathway. Moreover, SNAI2 small interfering RNA (siRNA) rescued SNAI2‐induced downregulation of AMTN gene expression, and TGFβ1‐induced AMTN gene expression was potentiated by SNAI2 siRNA. Taken together, these data demonstrated that AMTN gene expression in the promotion of EMT was downregulated by SNAI2. The inhibitory effect of AMTN gene expression was an independent feedback on the TGFβ1‐Smad3 signaling pathway, suggesting that the mechanism can be engaged in maintaining homeostasis of gingival epithelial cells at JE and the wound healing phase.

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“…5 Studies have confirmed that gingival hyperplasia is the result of reduced gingival epithelial cell death and/or increased proliferation, and it is speculated that apoptosis inhibition plays an important role in the development of fibrous epulis. 13,14 Although "Pathways in cancer" was listed as the first KEGG pathway in the current study, when all 71 DEGs categorized under this pathway were reanalyzed, the majority of the genes were also categorized under "Ras signaling" and "Regulation of programmed cell death." Therefore, the term "Pathways in cancer" identified in this study does not mean that gingival cells undergo the canonical cancer pathway in fibrous epulis but that they instead evade apoptosis and hyperproliferation.…”

Section: Discussionmentioning

confidence: 99%

The RAS‐PI3K‐AKT‐NF‐κB pathway transcriptionally regulates the expression of BCL2 family and IAP family genes and inhibits apoptosis in fibrous epulis

Jiang

Fang

et al. 2019

Clinical Laboratory Analysis

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Background Epulis has a tumor‐like appearance but is considered to be a massive reactive lesion rather than a true neoplasia. Limited information about the pathogenesis of epulis is available. The purpose of our study was to identify potential signaling pathways in fibrous epulis through transcriptome profiling. Methods Differentially expressed genes (DEGs) between fibrous epulis lesions and normal gingival tissues were detected using RNA sequencing (RNAseq). The expression levels of eighteen genes were validated using quantitative real‐time PCR (qRT‐PCR). Results RNAseq identified 533 upregulated genes and 732 downregulated genes. The top 10 upregulated genes were IL11, OSM, MMP3, KRT75, MMP1, IL6, IL1B, IL24, SP7, and ADGRG3. The top 10 downregulated genes were BCHE, TYR, DCT, KRT222, RP11‐507K12.1, COL6A5, PMP2, GFRA1, SCN7A, and CDH19. KEGG pathway analysis further indicated that the DEGs were enriched in “Pathways in cancer” and the “Ras signaling pathway”. quantitative real‐time PCR verified that the expression levels of SOS1, HRAS, PIK3CA, AKT3, IKBKA, IKBKB, NFKB1, BCL2, BCL2L1, XIAP, BIRC2, and BIRC3 were increased significantly. Conclusions The current transcriptomic profiling study reveals that in fibrous epulis, RAS‐PI3K‐AKT‐NF‐κB pathway transcriptionally regulates the expression of BCL2 family and IAP family genes, leading to increased proliferation and apoptosis inhibition.

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Amelotin gene expression is temporarily being upregulated at the initiation of apoptosis induced by TGFβ1 in mouse gingival epithelial cells

Cited by 13 publications

References 47 publications

Transcriptional regulation of human amelotin gene by interleukin‐1β

Transcriptional regulation of human amelotin gene by interleukin‐1β

Negative feedback by SNAI2 regulates TGFβ1‐induced amelotin gene transcription in epithelial–mesenchymal transition

The RAS‐PI3K‐AKT‐NF‐κB pathway transcriptionally regulates the expression of BCL2 family and IAP family genes and inhibits apoptosis in fibrous epulis

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