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Gene Review

Krt18  -  keratin 18

Mus musculus

Synonyms: CK-18, CK18, Cytokeratin endo B, Cytokeratin-18, Endo B, ...
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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


Biological context of Krt18


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


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


  1. Keratin-8 null mice have different gallbladder and liver susceptibility to lithogenic diet-induced injury. Tao, G.Z., Toivola, D.M., Zhong, B., Michie, S.A., Resurreccion, E.Z., Tamai, Y., Taketo, M.M., Omary, M.B. J. Cell. Sci. (2003) [Pubmed]
  2. Identification of the gene coding for the Endo B murine cytokeratin and its methylated, stable inactive state in mouse nonepithelial cells. Oshima, R.G., Trevor, K., Shevinsky, L.H., Ryder, O.A., Ceceña, G. Genes Dev. (1988) [Pubmed]
  3. Cytokeratin 8 protects from hepatotoxicity, and its ratio to cytokeratin 18 determines the ability of hepatocytes to form Mallory bodies. Zatloukal, K., Stumptner, C., Lehner, M., Denk, H., Baribault, H., Eshkind, L.G., Franke, W.W. Am. J. Pathol. (2000) [Pubmed]
  4. Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant. Ku, N.O., Michie, S., Oshima, R.G., Omary, M.B. J. Cell Biol. (1995) [Pubmed]
  5. Differential sensitivity of mouse epithelial tissues to the polyomavirus middle T oncogene. Cecena, G., Wen, F., Cardiff, R.D., Oshima, R.G. Am. J. Pathol. (2006) [Pubmed]
  6. Spontaneous losses of control of cytokeratin gene expression in transformed, non-epithelial human cells occurring at different levels of regulation. Knapp, A.C., Franke, W.W. Cell (1989) [Pubmed]
  7. Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice. Baribault, H., Penner, J., Iozzo, R.V., Wilson-Heiner, M. Genes Dev. (1994) [Pubmed]
  8. Activation of an intron enhancer within the keratin 18 gene by expression of c-fos and c-jun in undifferentiated F9 embryonal carcinoma cells. Oshima, R.G., Abrams, L., Kulesh, D. Genes Dev. (1990) [Pubmed]
  9. Thermochemotherapy for malignant melanoma: overcoming heterogeneity in drug sensitivity. Yamada, K., Someya, T., Shimada, S., Nakagawa, H., Kukita, A., Tokita, H., Tanaka, N. J. Invest. Dermatol. (1985) [Pubmed]
  10. Mechanism of action of the antitumour effect of K18. Fujii, T., Niimura, K., Furusho, T., Sugita, N., Oikawa, M., Takahashi, N., Yoshimura, M., Oguchi, Y., Iijima, H., Matsunaga, K. J. Int. Med. Res. (1989) [Pubmed]
  11. Differential effects between maotai and ethanol on hepatic gene expression in mice: possible role of metallothionein and heme oxygenase-1 induction by maotai. Liu, J., Cheng, M.L., Shi, J.Z., Yang, Q., Wu, J., Li, C.X., Waalkes, M.P. Exp. Biol. Med. (Maywood) (2006) [Pubmed]
  12. Keratins modulate c-Flip/extracellular signal-regulated kinase 1 and 2 antiapoptotic signaling in simple epithelial cells. Gilbert, S., Loranger, A., Marceau, N. Mol. Cell. Biol. (2004) [Pubmed]
  13. Disturbances in hepatic cell-cycle regulation in mice with assembly-deficient keratins 8/18. Toivola, D.M., Nieminen, M.I., Hesse, M., He, T., Baribault, H., Magin, T.M., Omary, M.B., Eriksson, J.E. Hepatology (2001) [Pubmed]
  14. Patterns of keratins 8, 18 and 19 during gonadal differentiation in the mouse: sex- and time-dependent expression of keratin 19. Appert, A., Fridmacher, V., Locquet, O., Magre, S. Differentiation (1998) [Pubmed]
  15. Targeted deletion of keratins 18 and 19 leads to trophoblast fragility and early embryonic lethality. Hesse, M., Franz, T., Tamai, Y., Taketo, M.M., Magin, T.M. EMBO J. (2000) [Pubmed]
  16. Phenotypic modulation of keratins, vimentin, and alpha-fetoprotein in cultured rat liver epithelial cells after chemical, oncogene, and spontaneous transformation. Bisgaard, H.C., Ton, P.T., Nagy, P., Thorgeirsson, S.S. J. Cell. Physiol. (1994) [Pubmed]
  17. Molecular cloning and characterization of the Endo B cytokeratin expressed in preimplantation mouse embryos. Singer, P.A., Trevor, K., Oshima, R.G. J. Biol. Chem. (1986) [Pubmed]
  18. Effects of keratin filament disruption on exocrine pancreas-stimulated secretion and susceptibility to injury. Toivola, D.M., Ku, N.O., Ghori, N., Lowe, A.W., Michie, S.A., Omary, M.B. Exp. Cell Res. (2000) [Pubmed]
  19. Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant. Ku, N.O., Michie, S.A., Soetikno, R.M., Resurreccion, E.Z., Broome, R.L., Oshima, R.G., Omary, M.B. J. Clin. Invest. (1996) [Pubmed]
  20. Differential tumorigenicity of two autologous human breast carcinoma cell lines, HMT-3909S1 and HMT-3909S8, established in serum-free medium. Petersen, O.W., van Deurs, B., Nielsen, K.V., Madsen, M.W., Laursen, I., Balslev, I., Briand, P. Cancer Res. (1990) [Pubmed]
  21. Bile acid-induced Mallory body formation in drug-primed mouse liver. Fickert, P., Trauner, M., Fuchsbichler, A., Stumptner, C., Zatloukal, K., Denk, H. Am. J. Pathol. (2002) [Pubmed]
  22. 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. Duan, W.R., Garner, D.S., Williams, S.D., Funckes-Shippy, C.L., Spath, I.S., Blomme, E.A. J. Pathol. (2003) [Pubmed]
  23. Type II keratins precede type I keratins during early embryonic development. Lu, H., Hesse, M., Peters, B., Magin, T.M. Eur. J. Cell Biol. (2005) [Pubmed]
  24. The Mallory body as an aggresome: in vitro studies. Riley, N.E., Li, J., Worrall, S., Rothnagel, J.A., Swagell, C., van Leeuwen, F.W., French, S.W. Exp. Mol. Pathol. (2002) [Pubmed]
  25. Relationships between intermediate filaments and cell-specific functions in renal cell lines derived from transgenic mice harboring the temperature-sensitive T antigen. Cluzeaud, F., Bens, M., Wu, M.S., Li, Z., Vicart, P., Paulin, D., Vandewalle, A. J. Cell. Physiol. (1996) [Pubmed]
  26. Differential expression of cytokeratin after orthotopic implantation of newly established human tongue cancer cell lines of defined metastatic ability. Morifuji, M., Taniguchi, S., Sakai, H., Nakabeppu, Y., Ohishi, M. Am. J. Pathol. (2000) [Pubmed]
  27. Conditionally immortalized mouse hepatocytes for use in liver gene therapy. Allen, K.J., Reyes, R., Demmler, K., Mercer, J.F., Williamson, R., Whitehead, R.H. J. Gastroenterol. Hepatol. (2000) [Pubmed]
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