Disease relevance of Krt18

• Hence, mouse gallbladder K8/K18/K19 expression is induced in response to cholelithiasis injury [1].
• However, in embryonal carcinoma cells, the Endo B beta 1 gene is undermethylated and in a relatively nuclease-sensitive conformation, but it is restricted by an additional, negative regulatory mechanism [2].
• Here we report that mice lacking the CK8 gene and hence CK intermediate filaments in hepatocytes, but still expressing the type I partner, ie, the CK18 gene, do not form MBs but suffer from extensive porphyria and progressive toxic liver damage, leading to the death of a considerable number of animals (7 of 12 during 12 weeks of intoxication) [3].
• Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant [4].
• PyMT expression induced by K18-driven Cre in internal epithelial organs resulted in pancreatic acinar metaplasia and ductal dysplasia with remarkable desmoplastic stromal responses in all 25 bitransgenic mice [5].

High impact information on Krt18

• We found that in SV40-transformed fibroblasts the CK 18 gene is constitutively transcribed into translatable mRNA but that the protein is rapidly degraded in the absence of its complex partner, CK 8 [6].
• 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 [7].
• Furthermore, induction of c-fos in a derivative of F9 cells results in increased expression of the endogenous mouse form of K18 [8].
• Cotransfection with c-jun or c-fos expression vectors had little effect on the expression of the K18 reporter construct in a parietal endodermal cell line already expressing the endogenous mouse gene [8].
• Cotransfection of F9 cells with K18 constructs that include the first intron and increasing amounts of an expression vector of c-jun results in a modest increase in the reporter gene expression [8].

Chemical compound and disease context of Krt18

• Whereas Endo W melanoma has no sensitivity, Endo B melanoma is sensitive to ACNU alone [9].
• This study measured the in vitro antitumour activity of K18, melphalan and immunoglobulin G on human myeloma cells (RPMI-8226) and the in vivo antitumour effects of K18 and melphalan in BALB/c nude mice bearing human lung cancer cells (LC-10) [10].
• The expression of genes related to liver fibrosis, such as cytokeratin-18, was slightly increased by the high dose of ethanol, but was unchanged in the Maotai group [11].

Biological context of Krt18

• 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 [12].
• Here, we report an additional abnormal liver phenotype, which is similar in K8 null, K18 null, and K18C mouse models [13].
• K18 and K8 continue to be detected in Sertoli cells during fetal life and after birth until 14 days postpartum [14].
• 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) [14].
• To investigate the mechanisms responsible for the restricted expression of Endo B, the gene coding for Endo B has been identified from among the five different Endo B genes found in the mouse genome by Southern hybridization analysis and cloning all or part of four of the genes [2].

Anatomical context of Krt18

• K18/19-deficient mouse embryos die earlier than any other intermediate filament knockouts reported so far, suggesting that keratins, in analogy to their well established role in epidermis, are essential for the integrity of a specialized embryonic epithelium [15].
• These findings have generated considerable confusion about the function of K8, K18 and K19 that are co-expressed in the mouse blastocyst and internal epithelia [15].
• In contrast, cell lines transformed spontaneously by prolonged passage in vitro expressed K18, while K14 and vimentin were absent [16].
• In the mouse, in contrast to the rat, keratins are detected in adult ovaries, and K18 is found in undifferentiated gonads and in ovaries [14].
• K18 is, thus, not specific to the testis in the mouse, as it is in the rat [14].

Associations of Krt18 with chemical compounds

• Endo B mRNA was detectable in RNA isolated from F9 cells treated with retinoic acid for 48 h [17].
• In contrast, pancreatic keratin disruption in transgenic mice that express keratin 18 Arg89 --> Cys (K18C) is not associated with an obvious pancreatic pathology [18].
• Here we show that mutant K18 expressing transgenic mice are highly susceptible to hepatotoxicity after acute administration of acetaminophen (400 mg/Kg) or chronic ingestion of griseofulvin (1.25% wt/wt of diet) [19].
• This subline was aneuploid, typically epithelial in morphology, and expressed keratins K8 and K18 and the glycoprotein MAM-6, typical of luminal epithelial cells in the normal breast gland [20].
• 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 [21].

Enzymatic interactions of Krt18

• Comparison of immunohistochemistry for activated caspase-3 and cleaved cytokeratin 18 with the TUNEL method for quantification of apoptosis in histological sections of PC-3 subcutaneous xenografts [22].

Other interactions of Krt18

• From E9.25 to E9.75, K5 forms atypical filaments with K18 [23].
• Following the accumulation of K18 protein at E3.5, keratin filaments are formed [23].
• Simple epithelial tissues such as liver and pancreas express keratins 8 (K8) and 18 (K18) as their major intermediate filament proteins [13].
• These results support the concept that MBs are aggresomes of CK 8 and CK18 and are a result of inhibition of the ubiquitin-proteasome pathway of protein degradation possibly caused by UBB+1 [24].
• Vimentin was still present in mesangial-like cells, but the proximal, distal, and collecting tubule cells contained uniform networks of cytokeratins K8-K18 and desmoplakin I and II around the cell peripheries [25].

Analytical, diagnostic and therapeutic context of Krt18

• Molecular cloning and characterization of the Endo B cytokeratin expressed in preimplantation mouse embryos [17].
• The phosphorylation increase in normal K18 after griseofulvin feeding appears to involve sites that are different to those that increase after partial hepatectomy [19].
• Mice expressing mutant K18 provide a novel animal model for human chronic hepatitis, and for studying the tissue specific function(s) of K8/18 [4].
• By Western blot analysis, nonmetastatic clone SQUU-A expressed cytokeratin (CK)13/4, 14, 16/6, 18/8, and 19, whereas a high metastatic clone SQUU-B expressed CK18/8 and 19 [26].
• RESULTS: All immortohepatocytes in culture stained positive by immunohistochemistry for the hepatocyte markers albumin, AFP, CK8 and CK18 [27].

References