Keratin 20 Helps Maintain Intermediate Filament Organization in Intestinal Epithelia

Zhou, Qin; Toivola, Diana M.; Feng, Ningguo; Greenberg, Harry B.; Franke, Werner W.; Omary, M. Bishr

doi:10.1091/mbc.e03-02-0059

Cited by 86 publications

(93 citation statements)

References 34 publications

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“…In accordance with previous literature, in WT mouse colon, cytokeratin (CK)20 expression was essentially absent from cells at the base of the crypt. Expression of CK20 was found in the more differentiated suprabasal regions, mainly on the upper surface and in scattered cells on the surface (20). In ER␤ Ϫ/Ϫ mice, there was an overall decrease in CK20 expression (Fig.…”

Section: Measurement Of Epithelial Cellular Proliferation and Migrationmentioning

confidence: 88%

Role of estrogen receptor β in colonic epithelium

Wada-Hiraike

Imamov

Hiraike

et al. 2006

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

228

177

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Several papers report that the colon is one of the tissues regulated by estrogen receptor (ER)β. To better understand the physiological role of ERβ in colonic tissue, we have compared morphology, proliferation, and differentiation of colonic epithelium in ERβ −/− mice and WT littermates. BrdUrd labeling revealed that the number of proliferating cells was higher in ERβ −/− mice and that the migration of labeled cells toward the luminal surface was faster in ERβ −/− mice than in WT littermates. Additionally, in the absence of ERβ, there was a decrease in apoptosis, which was measured by immunohistochemical staining of cleaved caspase-3. The state of differentiation of the colonic epithelial cells was studied by using epithelial markers. In ERβ −/− mice, there was a significant decrease in the expression of the differentiation marker cytokeratin (CK)20 and in the cellular adhesion molecules α-catenin (an adherens junction protein) and plectin (a hemidesmosomal protein). These changes were also evident by electron microscopy as abnormalities in tight junctions and in the number and shape of desmosomes in ERβ −/− mice. These findings suggest a role for ERβ in the organization and architectural maintenance of the colon. Furthermore, our results indicate that the rapidly proliferating cells of the colonic epithelium in ERβ −/− mice are lost by increased shedding and not by increased apoptosis. In this way, hyperproliferative cells that lack ERβ do not form hyperplastic lesions and do not accumulate in the superficial epithelium.

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Section: Measurement Of Epithelial Cellular Proliferation and Migrationmentioning

confidence: 88%

Role of estrogen receptor β in colonic epithelium

Wada-Hiraike

Imamov

Hiraike

et al. 2006

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

228

177

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“…As KRT20 is expressed in the epithelial cells of the crypt, it has been widely studied as a marker of differentiation in normal epithelium and colorectal cancer (CRC) samples (6)(7)(8)(9). Previous studies have suggested that KRT20 is phosphorylated in association with mucin secretion and filament organization (10,11). Transgenic mice with mutations at a conserved Arg to His site (R80H) show collapse of intermediate filaments.…”

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confidence: 99%

Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

Chan

Wong

Liu

et al. 2009

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

104

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CDX1 is a transcription factor that plays a key role in intestinal development and differentiation. However, the downstream targets of CDX1 are less well defined than those of its close homologue, CDX2. We report here the identification of downstream targets of CDX1 using microarray gene-expression analysis and other approaches. Keratin 20 (KRT20), a member of the intermediate filament and a well-known marker of intestinal differentiation, was initially identified as one of the genes likely to be directly regulated by CDX1. CDX1 and KRT20 mRNA expression were significantly correlated in a panel of 38 colorectal cancer cell lines. Deletion and mutation analysis of the KRT20 promoter showed that the minimum regulatory region for the control of KRT20 expression by CDX1 is within 246 bp upstream of the KRT20 transcription start site. ChIP analysis confirmed that CDX1 binds to the predicted CDX elements in this region of the KRT20 promoter in vivo. In addition, immunohistochemistry showed expression of CDX1 parallels that of KRT20 in the normal crypt, which further supports their close relationship. In summary, our observations strongly imply that KRT20 is directly regulated by CDX1, and therefore suggest a role for CDX1 in maintaining differentiation in intestinal epithelial cells. Because a key feature of the development of a cancer is an unbalanced program of proliferation and differentiation, dysregulation of CDX1 may be an advantage for the development of a colorectal carcinoma. This could, therefore, explain the relatively frequent down regulation of CDX1 in colorectal carcinomas by hypermethylation.colorectal cancer ͉ epithelial ͉ cell lines ͉ methylation ͉ cancer stem cells M embers of the keratin family provide structural support for the cell. They are also involved in apoptosis and protect cells from stress (1). Mutations of some keratins lead to genetic diseases, for example, of the skin and the liver (2-4). Keratin 20 (KRT20), a member of the keratin family, has been cloned and classified as a type-I keratin with a highly conserved amino acid sequence (5). It is mainly expressed in the cytoplasm of epithelial cells in the small and large intestine and in Merkel cells of the skin (5). As KRT20 is expressed in the epithelial cells of the crypt, it has been widely studied as a marker of differentiation in normal epithelium and colorectal cancer (CRC) samples (6-9). Previous studies have suggested that KRT20 is phosphorylated in association with mucin secretion and filament organization (10, 11). Transgenic mice with mutations at a conserved Arg to His site (R80H) show collapse of intermediate filaments.Despite its clearly important functions in the intestine, little is known about the regulation of KRT20.CDX1 is a homeobox transcription factor that is important for intestinal development and is specifically expressed in the small and large intestine in both mice and humans (12-15). CDX1 plays a role in intestinal epithelial cell differentiation (16) and is down-regulated in a number of CRC-derived cell lines...

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Section: Introductionmentioning

confidence: 99%

“…Keratins (K) include the type I and type II IFs, and all epithelial cells express at least one type I and one type II keratins as obligate noncovalent heteropolymers (Moll et al, 1982;Schweizer et al, 2006). In simple-type epithelia, as found in the liver, pancreas, and intestine, the major keratins are K18/K19/K20 (type I) and K7/K8 (type II), with the K8/K18 pair being dominant depending on the tissue (Moll et al, 1982;Ku et al, 1999;Herrmann et al, 2003;Zhou et al, 2003).Keratin networks are versatile structures that undergo dynamic reorganization in response to a variety of intra-and extracellular cues. Posttranslational modifications and keratin-binding partners are essential in mediating such responses (Coulombe and Omary, 2002;Omary et al, 2006).…”

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confidence: 99%

Reg-II Is an Exocrine Pancreas Injury-Response Product That Is Up-Regulated by Keratin Absence or Mutation

Zhong

Strnad

Toivola

et al. 2007

MBoC

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The major keratins in the pancreas and liver are keratins 8 and 18 (K8/K18), but their function seemingly differs in that liver K8/K18 are essential cytoprotective proteins, whereas pancreatic K8/K18 are dispensable. This functional dichotomy raises the hypothesis that K8-null pancreata may undergo compensatory cytoprotective gene expression. We tested this hypothesis by comparing the gene expression profile in pancreata of wild-type and K8-null mice. Most prominent among the up-regulated genes in K8-null pancreas was mRNA for regenerating islet-derived (Reg)-II, which was confirmed by quantitative reverse transcription-polymerase chain reaction and by an anti-Reg-II peptide antibody we generated. Both K8-null and wild-type mice express Reg-II predominantly in acinar cells as determined by in situ hybridization and immunostaining. Analysis of Reg-II expression in various keratin-related transgenic mouse models showed that its induction also occurs in response to keratin cytoplasmic filament collapse, absence, or ablation of K18 Ser52 but not Ser33 phosphorylation via Ser-to-Ala mutation, which represent situations associated with predisposition to liver but not pancreatic injury. In wild-type mice, Reg-II is markedly up-regulated in two established pancreatitis models in response to injury and during the recovery phase. Thus, Reg-II is a likely mouse exocrine pancreas cytoprotective candidate protein whose expression is regulated by keratin filament organization and phosphorylation. INTRODUCTIONIntermediate filaments (IFs), microfilaments, and microtubules are the three major cytoskeletal protein groups of mammalian cells (Bershadsky and Vasiliev, 1988;Ku et al., 1999). All IFs share a common prototype structure consisting of a coiled-coil ␣-helical rod domain that is interrupted by linkers and flanked by non-␣-helical N-terminal "head" and C-terminal "tail" domains (Fuchs and Cleveland, 1998;Herrmann et al., 2003;Coulombe and Wong, 2004;Herrmann and Aebi, 2004). Within the IF family, keratins are the largest subfamily, and they make up the IFs of epithelial cells, whereas other IFs are characteristic of unique cell types (e.g., desmin in myocytes, neurofilaments in neuronal cells). This tissue-specific expression reflects the involvement of IFs in a broad range of tissue-selective human diseases (Fuchs and Cleveland, 1998;Omary et al., 2004). Keratins (K) include the type I and type II IFs, and all epithelial cells express at least one type I and one type II keratins as obligate noncovalent heteropolymers (Moll et al., 1982;Schweizer et al., 2006). In simple-type epithelia, as found in the liver, pancreas, and intestine, the major keratins are K18/K19/K20 (type I) and K7/K8 (type II), with the K8/K18 pair being dominant depending on the tissue (Moll et al., 1982;Ku et al., 1999;Herrmann et al., 2003;Zhou et al., 2003).Keratin networks are versatile structures that undergo dynamic reorganization in response to a variety of intra-and extracellular cues. Posttranslational modifications and keratin-binding partners...

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Keratin 20 Helps Maintain Intermediate Filament Organization in Intestinal Epithelia

Cited by 86 publications

References 34 publications

Role of estrogen receptor β in colonic epithelium

Role of estrogen receptor β in colonic epithelium

Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

Reg-II Is an Exocrine Pancreas Injury-Response Product That Is Up-Regulated by Keratin Absence or Mutation

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