Disease relevance of KRT18

• We recently described transgenic mice that express point-mutant human K18 (Ku, N.-O., S. Michie, R.G. Oshima, and M.B. Omary. 1995. J. Cell Biol. 131:1303-1314) and develop chronic hepatitis and hepatocyte fragility in association with hepatocyte keratin filament disruption [1].
• Mutation of human keratin 18 in association with cryptogenic cirrhosis [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].
• Anti-CK18 antibodies reduced the binding and internalization of 125I-TAT by rat hepatoma cells [4].
• To study molecular changes, K8 and K18 were purified from surgically removed colon cancer and normal epithelia tissues [5].
• Docetaxel induced increased levels of caspase-cleaved CK18 in serum from breast cancer patients, indicating apoptosis [6].

Psychiatry related information on KRT18

• The latency period for biochemical relapse was 1481 days (median) in the CK 18-negative group and 1106 days (median) in the CK 18-positive group [7].
• Monitoring of different CK18 forms in peripheral blood during chemotherapy of prostate cancer patients showed individual differences in the patterns of release [8].
• We investigated the distribution and fate of apoptotic bodies during human development and in the adult, using an antibody (M30) that recognizes a neo-epitope formed early in the apoptotic cascade by caspase cleavage of cytokeratin 18 [9].

High impact information on KRT18

• 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 [10].
• To identify potential regulatory elements of the human K18 gene, various recombinant constructions were expressed in cultured cells [11].
• Three neoplastic cell lines (colonic and esophageal) with varying degrees of expression of cytokeratin-18 were used [12].
• An immunocytochemical assay for the epithelial cytokeratin protein (CK18) may fill this gap since it is a feature of epithelial cells but would not normally be in bone marrow [13].
• In addition, both caspase-3 activation and K18 cleavage was inhibited by expression of DEDDDeltaNLS1-3, a cytosolic form of DEDD that cannot be ubiquitinated [14].

Chemical compound and disease context of KRT18

• Seven of the 11 patients had mutations previously described in patients with cryptogenic cirrhosis: K8 Tyr-53 --> His, K8 Gly-61 --> Cys, and K18 His-127 --> Leu [15].
• In order to distinguish between basal and intermediate cells, and to assess the effects of androgen deprivation on prostate cancer, 56 human prostate cancer metastases and three cancer cell lines were characterized using antibodies to K5, K14, K18, and the neuroendocrine marker chromogranin A (ChA) [16].
• With these results, we propose that K18 as a new therapeutic target and curcumin, and/or its analogs, might be considered as potential therapeutic agents for cystic fibrosis [17].
• Absence of total filaments (K8-null) or CF (K18-null) does not increase susceptibility to pancreatitis induced by caerulein or a choline-deficient diet [18].
• The adenocarcinomas (n = 5), the solid carcinomas (n = 2), and the carcinosarcoma (n = 1) showed heterogeneous labelling with the MoAbs specific for luminal cell antigens in the normal canine mammary gland, i.e., K 18, K 7 and K 19 MoAbs [19].

Biological context of KRT18

• Our data demonstrate that a KRT18-driven expression vector delivered systemically can target gene expression to CF-affected tissues, despite an uneven distribution of plasmid DNA [20].
• We delivered a KRT18-driven lacZ plasmid complexed with cationic liposomes intravenously to mice and examined expression in various tissues [20].
• Dynamics of human keratin 18 phosphorylation: polarized distribution of phosphorylated keratins in simple epithelial tissues [21].
• In addition, ser52 of human K18 is a highly dynamic phosphorylation site that undergoes modulation during the S and G2/M phases of the cell cycle in association with filament reorganization [21].
• We have now identified human TNF receptor type 1 (TNFR1)-associated death domain protein (TRADD) to be the K18-interacting protein [22].

Anatomical context of KRT18

• Endogenous TRADD coimmunoprecipitated with K18, and colocalized with K8/18 filaments in human mammary epithelial cells [22].
• 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 [5].
• Cytokeratin 18 is expressed on the hepatocyte plasma membrane surface and interacts with thrombin-antithrombin complexes [4].
• The cancer-associated forms of K8 and K18 are specifically recognized by the human antibody, COU-1, cloned from the B cells of a cancer patient [5].
• Northern analysis detected CK 18 mRNA in extracts from 2/4 astrocytic cell lines [23].

Associations of KRT18 with chemical compounds

• Using chemical analysis, the stoichiometry of glycosylation was found to be 1.5 and 2 molecules of N-acetylglucosamine/protein molecule of CK8 and CK18, respectively [24].
• Acid hydrolysis of CK8 and CK18, purified from [3H]glucosamine-labeled cells, generated free glucosamine [24].
• Transfection of K8 Ser-73 --> Ala or K8 Ser-73 --> Asp with K18 generates normal-appearing filaments [25].
• In this system we used a human cytokeratin 18 expression cassette to drive epithelium-specific expression of the reverse tetracycline transactivator (rtTA), which turns on CFTR expression from a Tet-inducible promoter in the presence of doxycycline [26].
• The majority of luminal cells expressed K18(++), but colocalization of K5+/18(++) were recognized [27].

Physical interactions of KRT18

• The COOH-terminal region of TRADD interacted with the coil Ia of the rod domain of K18 [22].
• 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 [5].
• However, when K8 or K18 bound to nitrocellulose were incubated with complementary keratin they became reactive with this antibody [28].

Enzymatic interactions of KRT18

• During viral replication, all of vimentin were degraded and phosphorylated keratin 18 increased [29].

Regulatory relationships of KRT18

• KRT18 is naturally expressed in a spatial pattern similar to that of CFTR, the gene mutated in CF [20].
• Epithelium-specific ets transcription factor 2 upregulates cytokeratin 18 expression in pulmonary epithelial cells through an interaction with cytokeratin 18 intron 1 [30].
• No difference was noted in the levels of IgG or IgM antibodies to CK-18 or EPK between controls and patients with OA or RA [31].
• 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].
• When the epithelial cytokeratin pair 8 and 18 was expressed in the nucleus via an engineered NLS in the cytokeratin 18 gene, more network-like, extended filament arrays were generated [33].

Other interactions of KRT18

• Among IF proteins tested in two-hybrid systems, TRADD specifically bound K18 and K14, type I (acidic) keratins [22].
• The four remaining patients had mutations at one K8 and three other K18 new sites [15].
• In immortalized cells, which are preneoplastic or partially transformed, the levels of K5 mRNA and protein are lower than in normal cells, whereas the amount of K18 is increased [34].
• In contrast, in both AC and ASC, the CK18 protein was diffusely distributed within the cytoplasm, and DP showed both membranous and cytoplasmic localization [35].
• Immunofluorescence analysis revealed the expression of albumin (ALB) and cytokeratin-18 (CK-18) [36].

Analytical, diagnostic and therapeutic context of KRT18

• A KRT18-based vector may be a useful alternative to viral promoter-based vectors in clinical gene therapy trials to treat CF [20].
• 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 [5].
• A mixture of K8 and K18 in solution also reacted strongly with the MAb LE61 in ELISA [28].
• We investigated the mechanical properties of K8-K18 filament suspensions using rheological assays in conjunction with light and electron microscopy [37].
• 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) [38].

References