Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients

Owens, DW; Wilson, Neil; Hill, Alison; Rugg, Elizabeth L.; Porter, Rebecca; Hutcheson, Aileen M.; Quinlan, Roy A.; Heel, David A. van; Parkes, Miles; Jewell, D P; Campbell, Simon; Ghosh, Subrata; Satsangi, Jack; Lane, E. Birgitte

doi:10.1242/jcs.01043

Cited by 88 publications

(93 citation statements)

References 63 publications

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“…Our present studies indicate that IFs play a scaffolding role in tissue-specific functions beyond their traditional "mechanical strength" functions. Understanding how IFs act as organizers of the apical domain in intestinal cells and their relationships with other mechanisms of polarization may provide critical insights into the consequences of mutations in various keratins identified as determinants of bowel, liver, and pancreatic disease in humans (Cavestro et al, 2003;Ku et al, 2003;Owens et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Intermediate Filaments Interact with Dormant Ezrin in Intestinal Epithelial Cells

Wald

Oriolo

Casanova

et al. 2005

MBoC

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Ezrin connects the apical F-actin scaffold to membrane proteins in the apical brush border of intestinal epithelial cells. Yet, the mechanisms that recruit ezrin to the apical domain remain obscure. Using stable CACO-2 transfectants expressing keratin 8 (K8) antisense RNA under a tetracycline-responsive element, we showed that the actin-ezrin scaffold cannot assemble in the absence of intermediate filaments (IFs). Overexpression of ezrin partially rescued this phenotype. Overexpression of K8 in mice also disrupted the assembly of the brush border, but ezrin distributed away from the apical membrane in spots along supernumerary IFs. In cytochalasin D-treated cells ezrin localized to a subapical compartment and coimmunoprecipitated with IFs. Overexpression of ezrin in undifferentiated cells showed a Triton-insoluble ezrin compartment negative for phospho-T567 (dormant) ezrin visualized as spots along IFs. Pulse-chase analysis showed that Triton-insoluble, newly synthesized ezrin transiently coimmunoprecipitates with IFs during the first 30 min of the chase. Dormant, but not active (p-T567), ezrin bound in vitro to isolated denatured keratins in Far-Western analysis and to native IFs in pull-down assays. We conclude that a transient association to IFs is an early step in the polarized assembly of apical ezrin in intestinal epithelial cells. INTRODUCTIONEzrin, a member of the ezrin-radixin-moesin (ERM) family, is a conspicuous component of the apical F-actin-based scaffold in simple epithelial cells. It connects NHERF/EBP-50 (which in turn binds important membrane proteins such as CFTR and NHE-3) to F-actin and also enables protein kinase A-mediated regulation of apical channels (Kurashima et al., 1999;Louvet-Vallée, 2000;Weinman et al., 2000Weinman et al., , 2001. Because ezrin is the earliest protein of this complex scaffold to be recruited, it has long been considered as an organizer of the brush border (Bretscher et al., 1997). In support of that view, ezrin knockout mice show a distinctive brush-border phenotype with much shorter microvilli that resemble undifferentiated stages (Saotome et al., 2004). Furthermore, expression of ezrin in fibroblasts is sufficient to organize microvilli (Shaw et al., 1998). After translation, ezrin initially adopts a "dormant" configuration, in which the C-and N-terminal domains bind to each other. On phosphorylation in T567, it changes to an open "active" configuration, freeing the C-terminal domain (C-ERMAND) to bind F-actin and the N-terminal domain (N-ERMAND) to bind NHERF or transmembrane proteins (Bretscher et al., 2000). Although the mechanism of activation and assembly of ezrin has been studied in great detail by several groups, the mechanisms that ensure that ezrin assembly occur mostly under the apical membrane of simple epithelial cells remain obscure. Fievet et al. (2004) have shown that binding to phosphatidylinositol 4,5-diphosphate (PIP 2 ) is a prerequisite for activation. However, PIP 2 is not known to be apically polarized in epithelial cells, rather it is basol...

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Section: Discussionmentioning

confidence: 99%

Intermediate Filaments Interact with Dormant Ezrin in Intestinal Epithelial Cells

Wald

Oriolo

Casanova

et al. 2005

MBoC

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“…The critical importance of cytokeratin filaments to the resilience and function of epithelia has been established by the discovery of naturally occurring cytokeratin mutations in various diseases (McGowan and Coulombe, 1998;Owens et al, 2004). The members of the cytokeratin 6 family have been associated with chronic hyperproliferative disorders of the skin as well as in carcinomas of urinary bladder, esophagus and other epithelia (McGowan and Coulombe, 1998).…”

Section: Discussionmentioning

confidence: 99%

Identification of a stem cell candidate in the normal human prostate gland

Schmelz

Moll

Hesse

et al. 2005

European Journal of Cell Biology

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Stem cells of the human prostate gland have not yet been identified utilizing a structural biomarker. We have discovered a new prostatic epithelial cell phenotype-expressing cytokeratin 6a (Ck6a+ cells). The Ck6a+ cells are present within a specialized niche in the basal cell compartment in fetal, juvenile and adult prostate tissue, and within the stem cell-enriched urogenital sinus. In adult normal prostate tissue, the average abundance of Ck6a+ cells was 4.9%. With proliferative stimuli in the prostate organ culture model, in which the epithelial-stromal interaction was maintained, a remarkable increase of Ck 6a expression was noticed to up to 64.9%. The difference in cytokeratin 6a expression between the normal adult prostate and the prostate organ culture model was statistically significant (p<0.0001). Within the prostate organ culture model the increase of cytokeratin 6a-expressing cells significantly correlated with increased proliferation index (r = 0.7616; p = 0.0467) The Ck6a+ cells were capable of differentiation as indicated by their expression of luminal cell markers such as ZO-1 and prostate specific antigen (PSA). Our data indicate that Ck6a+ cells represent a prostatic epithelial stem cell candidate possessing high potential for proliferation and differentiation. Since the development of benign prostatic hyperplasia and prostate carcinogenesis are disorders of proliferation and differentiation, the Ck6a+ cells may represent a major element in the development of these diseases.

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“…Several studies have indicated that KRT8-null mice suffer chronic inflammation (Baribault et al, 1994;Habtezion et al, 2005). Thus, mutation of KRT8 in humans also leads to epithelial instability in the gut and may play a role in IBD (Owens et al, 2004). Furthermore, Treton et al, described changes in protein translation that altered colonic epithelial barrier function involving KRT8, from the results of genome-wide microarray analysis of polysome-bound messenger RNA from UC patients (Treton et al, 2011).…”

Section: Continued) Differentially Expressed Proteins In the Colon Mmentioning

confidence: 99%

Preventive Effects of Spirogyra neglecta and a Polysaccharide Extract against Dextran Sodium Sulfate Induced Colitis in Mice

Taya

Kakehashi²,

Wongpoomchai³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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Ulcerative colitis (UC) results from colonic epithelial barrier defects and impaired mucosal immune responses. In this study, we aimed to investigate the modifying effects of a Spirogyra neglecta extract (SNE), a polysaccharide extract (PE) and a chloroform fraction (CF) on dextran sodium sulfate (DSS)-induced colitis in mice and to determine the mechanisms. To induce colitis, ICR mice received 3% DSS in their drinking water for 7 days. Seven days preceding the DSS treatment, oral administration of SNE, PE and CF at doses of 50, 25 and 0.25 mg/kg body weight (low dose), 200, 100 and 1 mg/kg body weight (high dose) and vehicle was started and continued for 14 days. Histologic findings showed that DSS-induced damage of colonic epithelial structure and inflammation was attenuated in mice pre-treated with SNE, PE and CF. Furthermore, SNE and PE significantly protected colonic epithelial cells from DSS-induced cell cycle arrest, while SNE, PE and CF significantly diminished apoptosis. Proteome analysis demonstrated that SNE and PE might ameliorate DSS-induced colitis by inducing antioxidant enzymes, restoring impaired mitochondria function, and regulating inflammatory cytokines, proliferation and apoptosis. These results suggest that SNE and PE could prevent DSS-induced colitis in ICR mice by protection against and/or aiding recovery from damage to the colonic epithelium, reducing ROS and maintaining normal mitochondrial function and apoptosis.

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Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients

Cited by 88 publications

References 63 publications

Intermediate Filaments Interact with Dormant Ezrin in Intestinal Epithelial Cells

Intermediate Filaments Interact with Dormant Ezrin in Intestinal Epithelial Cells

Identification of a stem cell candidate in the normal human prostate gland

Preventive Effects of Spirogyra neglecta and a Polysaccharide Extract against Dextran Sodium Sulfate Induced Colitis in Mice

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