Disease relevance of Krt8

• The function of intestinal keratins is unknown, although keratin 8 (K8)-null mice develop colitis, hyperplasia, diarrhea, and mistarget jejunal apical markers [1].
• The ConA-induced failure of the trophoblast giant cell barrier results in hematoma formation between the trophoblast giant cell layer and the embryonic yolk sac in a phenocopy of dying K8-deficient concepti in a sensitive genetic background [2].
• We studied disease progression, the inflammatory responses, and role of luminal bacteria in K8-null mice in order to characterize the intestinal pathology of K8-associated colitis [3].
• In PDV, PDVCM1, PDVCM2, and PDVCV1 carcinomas the overall expression of K13 is higher than that of K8 [4].
• To ascertain a potential function for simple epithelium keratins in mammary adenocarcinoma in vivo, keratin-8-deficient mice (mK8) were mated with transgenic mice carrying the middle T oncogene driven by the MMTV promoter [5].

High impact information on Krt8

• Our results demonstrate that genetic modifiers of K8/K18 filament functions, with profound effects on embryogenesis and gut functional integrity, are differentially active in the FVB/N and C57B1/6 genetic backgrounds [6].
• Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice [6].
• The intermediate filament protein keratin 8 (K8) is critical for the development of most mouse embryos beyond midgestation [2].
• We conclude the lethality of K8-/- embryos is due to a TNF-sensitive failure of trophoblast giant cell barrier function [2].
• In vivo, after injection into the cleared mammary fat pad, these cells gave rise to bilayered, hollow, alveolus-like structures comprising basal cells expressing cytokeratin 5 and luminal cells positive for cytokeratin 8 and secreting beta-casein in a polarized manner into the lumen [7].

Chemical compound and disease context of Krt8

• This CpG cluster region was found to be hypomethylated in endodermal PYS-2 cells, retinoic acid-treated F9 cells, and F9 embryonal carcinoma cells, but hypermethylated in BALB/C 3T3 fibroblast cells that do not express EndoA [8].

Biological context of Krt8

• Functional studies with different cell models have suggested that K8/K18 are involved in simple epithelial cell resistance to several forms of stress that may lead to cell death [9].
• Here, we report an additional abnormal liver phenotype, which is similar in K8 null, K18 null, and K18C mouse models [10].
• These effects could stem from disturbed functions of K8/18-dependent cell-cycle regulators, such as the signaling integrator, 14-3-3 [10].
• Analysis of normal gut-specific homing molecules, reveals an increased number of alpha(4)beta(7)-positive cells and vascular mucosal addressin cell adhesion molecule-1 in K8-null colons [3].
• EndoA cytokeratin (EndoA) belongs to a family of intermediate filaments (IFs) and is coordinately expressed with EndoB cytokeratin during early mouse embryogenesis [11].

Anatomical context of Krt8

• These hepatocyte cytoplasmic deposits are composed primarily of hyperphosphorylated keratins 8 and 18 (K8/K18) [12].
• Colon lymphocytes were isolated for analysis of their phenotype and cytokine production, and vascular and lymphocyte adhesion molecule expression in K8-/- mice of varying ages [3].
• In tumors induced by the cell lines upon injection in mice, K8 is found in the less differentiated regions as opposite to K13, restricted to the differentiating areas of the tumors [4].
• Immunocytochemical analysis of the cells in monolayer demonstrated that K8 as well as K14 were incorporated in the cellular cytoskeleton [13].
• It demonstrates that the latency, but not the incidence nor the morphological features, of PyV middle T-induced mammary gland tumours is affected by keratin 8 deficiency [5].

Associations of Krt8 with chemical compounds

• Labeling for K8/18 of luminal cells was heterogeneous at all times [14].
• Similarly, cytokeratin-8 (CK-8) levels were markedly increased in the liver homogenates of rats fed ethanol when given PS-341 [15].
• Antibodies to specific serine phosphorylated sites 73 and 431, located in cytokeratin 8, localized to Mallory bodies in vivo, indicating that cytokeratin 8 was hyperphosphorylated [16].
• Furthermore, differentiation in presence of Bt2cAMP plus RA resulted in an earlier induction of the two mRNAs and a higher level of expression of K8 mRNA [17].
• Like DDC refeeding, both CBDL and CA feeding of drug-primed mice significantly increased CK 8 and CK 18 mRNA and protein levels (with excess of CK 8) and resulted in ubiquitination and abnormal phosphorylation of CKs [18].

Physical interactions of Krt8

• In this report we show that GST-c-Ets-1 fusion protein binds specifically to the EndoA enhancer unit sequence by gel shift analysis [19].
• Mutations that impair Ets-2 binding abolished the activity of the EndoA enhancer [20].
• We have employed a novel vaccination strategy using a secreted protein, chlamydial protease-like activity factor (CPAF), which has been shown to degrade host major histocompatibility complex transcription factors and keratin-8 and therefore may allow immune evasion and establishment of a productive infection [21].

Co-localisations of Krt8

• On the other hand, K8 does not generally colocalize with K13, a keratin also aberrantly expressed by epidermal cell cultures when induced to differentiate by high Ca2+ medium [4].

Regulatory relationships of Krt8

• Simple epithelial tissues such as liver and pancreas express keratins 8 (K8) and 18 (K18) as their major intermediate filament proteins [10].
• Keratin 8 and gamma-glutamyltranspeptidase were expressed only in alpha 6 beta 4 positive cells [22].
• Moreover, altering Fas trafficking by disrupting microtubules with colchicine reduces by twofold the protection generated against Jo2-induced lethal action in K8-null versus WT hepatocytes [23].
• Ets-1 also moderately activated the EndoA enhancer [19].
• These data show that Ets-2 related protein binds and activates the EndoA enhancer in a sequence-specific fashion [20].

Other interactions of Krt8

• The lethality resulted from defects in the placenta where both K19 and K8 are normally expressed [24].
• In contrast, K6, K8, K13 and K14 are constitutively expressed even when squamous differentiation is not observed [25].
• In colonies of both phenotypes, only a few cells expressed K5 and bcl-2, while all cells expressed K8 [26].
• Our ICC assay showed that differentiating cells did not express hepatic proteins, such as AFP, ALB, CK8, and CK18 until day 7, day 9, day 11, and day 11, respectively (up to 2 days later when growth factors are not present) [27].
• The cells were double stained using CK-8 and ubiquitin antibodies [28].

Analytical, diagnostic and therapeutic context of Krt8

• Sequence analysis reveals that EndoA is composed of 490 amino acids, its Mr is 54,362, and it contains a central alpha-helical coiled-coil structure flanked by non-alpha-helical domains [11].
• Further analysis by immunoprecipitation showed that filament complexes were formed between K8 and K14 as atypical partners [13].
• To extend these findings, we have undertaken a study of the expression of genes encoding for K18 and K19 and their basic partner K8 in the mouse from 10.5 days of gestation until adulthood, using immunofluorescence, in situ hybridization, and reverse transcriptase polymerase chain reaction (RT-PCR) [29].
• Secondly, after electroporation of a construct containing the K14 promoter driving nuclear GFP into the epithelium of E15.5 oesophagus, some cells expressed both K8 and GFP [30].
• Double-label immunofluorescence staining using TROMA-1 and RK13 antibodies demonstrated that K8 did not generally colocalize with K13, a keratin normally found in internal stratified epithelial but aberrantly expressed in mouse epidermal tumors [31].

References