Disease relevance of KRT8

• Also, ectopic expression of epidermal K14 in mouse liver results in chronic hepatitis, and disruption of mouse K8 leads to embryo lethality with extensive liver hemorrhage [1].
• This moderation of the effects of TNF may be the fundamental function of K8 and K18 common to liver regeneration, inflammatory bowel disease, hepatotoxin sensitivity, and the diagnostic, persistent expression of these keratins in many carcinomas [2].
• K8-deficient (K8(-)) mice, which escape embryonic lethality, develop inflammatory colorectal hyperplasia, mild liver abnormalities, and tolerate hepatectomy poorly [2].
• Studies of liver explants from a large cohort of U.S. patients showed that K8/K18 mutations confer a risk to developing end-stage liver diseases, though which diseases are preferentially involved is unknown [3].
• Notably, there was a significant association of exonic, but not of intronic K8 variants with increased fibrosis [3].

Psychiatry related information on KRT8

• Human kallikrein 8 (hK8), whose gene was originally cloned as the human ortholog of a mouse brain protease, is known to be associated with diseases such as ovarian cancer and Alzheimer's disease [4].

High impact information on KRT8

• We have previously described a mutation in the keratin 18 gene in a patient with cryptogenic cirrhosis, but the importance of mutations in the keratin 8 and keratin 18 genes in such patients is unclear [5].
• Keratin 8 mutations in patients with cryptogenic liver disease [5].
• The mouse forms of human keratins 18 and 8 (K18 and K8) are the first members of the large intermediate filament gene family to be expressed during embryogenesis [6].
• Keratins K8 and K18 are the major components of the intermediate-filament cytoskeleton of simple epithelia [7].
• In this study, we have characterized a Japanese variant of Glanzmann thrombasthenia, KO, whose platelets express normal amounts of alphaIIb beta3 [8].

Chemical compound and disease context of KRT8

• RESULTS: Of the 55 patients with cryptogenic liver disease, 3 had glycine-to-cysteine mutations at position 61 (a highly conserved glycine) of keratin 8, and 2 had tyrosine-to-histidine mutations at position 53 of keratin 8 [5].
• Of the 349 blood bank control samples, only one contained the Tyr-53 --> His and one the Gly-61 --> Cys K8 mutations (P < 0.004 when comparing cirrhosis versus control groups) [9].
• Absence of total filaments (K8-null) or CF (K18-null) does not increase susceptibility to pancreatitis induced by caerulein or a choline-deficient diet [10].
• Fulvestrant treatment caused ERalpha degradation in CK8.CK18-positive human breast cancer cells, and CK8 and CK18 depletion by small interference RNAs partially blocked fulvestrant-induced receptor degradation [11].
• In the overwhelming majority of carcinomas, cells did not contain myoepithelial markers (keratin 17 and vimentin) but expressed only keratin 8 specific to normal luminal epithelium [12].

Biological context of KRT8

• These data suggested that shear stress mediates the phosphorylation of serine residues in K8, leading to the disassembly of IF in alveolar epithelial cells [13].
• Keratin 8 (K8) serine 73 occurs within a relatively conserved type II keratin motif ((68)NQSLLSPL) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis [14].
• Transfection of K8 Ser-73 --> Ala or K8 Ser-73 --> Asp with K18 generates normal-appearing filaments [14].
• The persistent expression of K8 and K18 may reflect the integrated transcriptional activation of such transcription factors and, in the cases of ectopic expression, an escape from the suppressive epigenetic mechanisms of DNA methylation and chromatin condensation [15].
• Cytokeratin 8 and 18 genotypes were specified by polymerase chain reaction (PCR) amplification and direct sequence analysis was used to detect the previously described mutations in cytokeratin 8 (G61C) and in cytokeratin 18 (Y53H) [16].

Anatomical context of KRT8

• Old K18 null mice, however, developed a distinctive liver pathology with abnormal hepatocytes containing K8-positive aggregates [17].
• We show that normal and malignant epithelial cells deficient in K8 and K18 are approximately 100 times more sensitive to TNF-induced death [2].
• A K8 cDNA containing all coding sequences was isolated and expressed in mouse fibroblasts either singly or in combination with K18 [18].
• In contrast to other cytokeratins, K8 and K18 are persistently expressed during malignant transformation, but changes in cell morphology are accompanied by alterations in the intermediate filament network [19].
• Mallory bodies (MBs) are cytoplasmic inclusions that contain keratin 8 (K8) and K18 and are present in hepatocytes of individuals with alcoholic liver disease, nonalcoholic steatohepatitis, or benign or malignant hepatocellular neoplasia [20].

Associations of KRT8 with chemical compounds

• Phosphoserine-specific antibodies demonstrate that K8 Ser-73 is phosphorylated in a time-dependent manner in shear-stressed AEC [13].
• These progenitor/stem cells differentiate into mature luminal cells by maintaining CK8 and CK18, and losing all other makers [21].
• Standard immunohistochemical methods were used to detect the presence of vimentin, cytokeratin 8, cytokeratin 18, macrophages and Langerhans cells in the human tonsillar epithelium in formalin-fixed and frozen tissue specimens [22].
• K8/19 tyrosine phosphorylation was confirmed by metabolic 32PO4-labeling followed by phosphoamino acid analysis, and by immunoblotting with anti-phosphotyrosine antibodies [23].
• Hyposmosis-induced dephosphorylation of K8 Ser431-P is inhibited by okadaic acid but not by tautomycin or cyclosporine [24].

Physical interactions of KRT8

• Using surface plasmon resonance, the affinity of COU-1 for this epitope was determined to be 10(9) x m(-1), i.e. more than 2 orders of magnitude higher than for intact heterotypic K8/K18 complexes [19].
• We report that the MAb LE65 does not recognize individual keratin polypeptides but it instead reacts with a complex of K8 with K18 [25].
• The plasminogen-binding site is located at the C-terminus of CK8 [26].
• K8/18-bound grp78 can be dissociated by Mg-ATP and the association can be reconstituted in vitro using purified grp78, then redissociated again by Mg-ATP [27].
• Normal nuclear morphology and k-8 immunofluorescence coupled with the lack of DNA laddering or other features of apoptosis indicated that K3-induced cytotoxicity, evident within 4 h of treatment and delayed but not prevented by MEK1/2 inhibition, was due to a form of stress-activated cell death known as oncosis [28].

Enzymatic interactions of KRT8

• Furthermore, K8 was also phosphorylated on Ser-73 by JNK in vitro, yielding similar phosphopeptide maps as the in vivo phosphorylated material [29].
• We show that K8 is strongly phosphorylated on Ser-73 upon stimulation of the pro-apoptotic cytokine receptor Fas/CD95/Apo-1 in HT-29 cells [29].
• The kinase activity coimmunoprecipitated with CK8 and 18 and phosphorylated immunoprecipitates of the CK [30].
• 2A proteinase of human rhinovirus cleaves cytokeratin 8 in infected HeLa cells [31].

Regulatory relationships of KRT8

• Kinase assays showed that c-Jun N-terminal kinase (JNK) was also activated with activation kinetics corresponding to that of K8 phosphorylation [29].
• Our results demonstrate a direct association of grp78 with K8 under conditions that induce grp78 expression [27].
• No change in cell morphology was noted after high levels of K8/18 were expressed in Sf9 cells coinfected with recombinant virus-containing human K8 and K18 [32].
• Adult human hepatocytes contain cytokeratin 8 and 18 whereas bile duct cells also express cytokeratin 7 and 19 in addition to cytokeratin 8 and 18 [33].

Other interactions of KRT8

• The epitope is revealed after proteolytic removal of the head domain of either K8 or K18 [19].
• Here we demonstrate, through the use of yeast two-hybrid assay, a specific interaction of the periplakin linker domain with keratin 8 and vimentin [34].
• In in vitro co-sedimentation assays, trichoplein directly binds to K8/18, but not with vimentin, desmin, actin filaments or microtubules [35].
• This study confirms the presence of antigen-presenting cells, macrophages and Langerhans cells in the tonsillar epithelium and shows that intermediate filament proteins, vimentin, cytokeratin 8 and 18 are unreliable markers for human tonsillar M-cells, if indeed such cells exist in human tonsils [22].
• CK18 may participate in the oligomer, together with CK8, based on its ability to bind t-PA [26].

Analytical, diagnostic and therapeutic context of KRT8

• Electron microscopy of in vitro assembled K18 H127L and wild type K8 showed an assembly defect as compared with normal K8/18 assembly [1].
• Immunoelectron microscopy of this tissue demonstrated the presence of typical K8/19 IF, thus highlighting in vivo that K19 is a fully competent partner for K8 [17].
• Western blotting and amino acid sequencing revealed the presence of abundant K8 and K18 fragments, truncated at the N terminus, from cancerous, but not normal, epithelial cells [19].
• A mixture of K8 and K18 in solution also reacted strongly with the MAb LE61 in ELISA [36].
• Cytokeratin 8 and vimentin, which were previously shown to be involved in the infection processes of other viruses, were further analyzed to confirm their in vivo interactions with the core protein by immunoblotting and immunofluorescence microscopy [37].

References