Gastroenterology
Volume 129, Issue 3 , Pages 885-893 , September 2005

Keratins as Susceptibility Genes for End-Stage Liver Disease

  • Nam–On Ku

      Affiliations

    • Department of Medicine, Palo Alto VA Medical Center, Palo Alto and Stanford University School of Medicine, Stanford, California
    • ,
  • Joseph K. Lim

      Affiliations

    • Department of Medicine, Palo Alto VA Medical Center, Palo Alto and Stanford University School of Medicine, Stanford, California
    • ,
  • Sheri M. Krams

      Affiliations

    • Department of Surgery, Palo Alto VA Medical Center, Palo Alto and Stanford University School of Medicine, Stanford, California
    • ,
  • Carlos O. Esquivel

      Affiliations

    • Department of Surgery, Palo Alto VA Medical Center, Palo Alto and Stanford University School of Medicine, Stanford, California
    • ,
  • Emmet B. Keeffe

      Affiliations

    • Department of Medicine, Palo Alto VA Medical Center, Palo Alto and Stanford University School of Medicine, Stanford, California
    • ,
  • Teresa L. Wright

      Affiliations

    • San Francisco VA Medical Center, San Francisco, California USAUniversity of California, San Francisco, California
    • ,
  • David A.D. Parry

      Affiliations

    • Massey University, Palmerston North, New Zealand
    • ,
  • M. Bishr Omary

      Affiliations

    • Department of Medicine, Palo Alto VA Medical Center, Palo Alto and Stanford University School of Medicine, Stanford, California
    • Corresponding Author InformationAddress requests for reprints to: Nam-On Ku, PhD, Palo Alto VA Medical Center, Mail Code 154J, 3801 Miranda Avenue, Palo Alto, California 94304. fax: (650) 852-3259.

Received 24 October 2004 ,Accepted 26 May 2005.

References 

  1. Moll R , Franke WW , Schiller DL , Geiger B , Krepler R . The catalog of human cytokeratins (patterns of expression in normal epithelia, tumors and cultured cells) . Cell . 1982;31:11–24
  2. Fuchs E , Weber K . Intermediate filaments (structure, dynamics, function, and disease) . Annu Rev Biochem . 1994;63:345–382
  3. Coulombe PA , Omary MB . “Hard” and “soft” principles defining the structure, function and regulation of keratin intermediate filaments . Curr Opin Cell Biol . 2002;14:110–122
  4. Herrmann H , Aebi U . Intermediate filaments (molecular structure, assembly mechanism, and integration into functionally distinct intracellular scaffolds) . Annu Rev Biochem . 2004;73:749–789
  5. Fuchs E , Cleveland DW . A structural scaffolding of intermediate filaments in health and disease . Science . 1998;279:514–519
  6. Omary MB , Coulombe PA , McLean WH . Intermediate filament proteins and their associated diseases . N Engl J Med . 2004;351:2087–2100
  7. Baribault H , Penner J , Iozzo RV , Wilson-Heiner M . Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice . Genes Dev . 1994;8:2964–2973
  8. Ku NO , Michie S , Oshima RG , Omary MB . Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant . J Cell Biol . 1995;131:1303–1314
  9. Omary MB , Ku NO , Toivola DM . Keratins (guardians of the liver) . Hepatology . 2002;35:251–257
  10. Caulin C , Ware CF , Magin TM , Oshima RG . Keratin-dependent, epithelial resistance to tumor necrosis factor-induced apoptosis . J Cell Biol . 2000;149:17–22
  11. Gilbert S , Loranger A , Daigle N , Marceau N . Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation . J Cell Biol . 2001;154:763–773
  12. Ku NO , Soetikno RM , Omary MB . Keratin mutation in transgenic mice predisposes to Fas but not TNF-induced apoptosis and massive liver injury . Hepatology . 2003;37:1006–1014
  13. Zatloukal K, Stumptner C, Lehner M, Denk H, Baribault H, Eshkind LG, et al. Cytokeratin 8 protects from hepatotoxicity, and its ratio to cytokeratin 18 determines the ability of hepatocytes to form Mallory bodies . Am J Pathol . 2000;156:1263–1274
  14. Ku NO , Wright TL , Terrault NA , Gish R , Omary MB . Mutation of human keratin 18 in association with cryptogenic cirrhosis . J Clin Invest . 1997;99:19–23
  15. Ku NO , Gish R , Wright TL , Omary MB . Keratin 8 mutations in patients with cryptogenic liver disease . N Engl J Med . 2001;344:1580–1587
  16. Ku NO, Darling JM, Krams SM, Esquivel CO, Keeffe EB, Sibley RK, et al. Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies . Proc Natl Acad Sci U S A . 2003;100:6063–6068
  17. Porter RM , Lane EB . Phenotypes, genotypes and their contribution to understanding keratin function . Trends Genet . 2003;19:278–285
  18. Ku NO , Omary MB . Phosphorylation of human keratin 8 in vivo at conserved head domain serine 23 and at epidermal growth factor-stimulated tail domain serine 431 . J Biol Chem . 1997;272:7556–7564
  19. Munoz V , Serrano L . Development of the multiple sequence approximation within the AGADIR model of alpha-helix formation (comparison with Zimm-Bragg and Lifson-Roig formalisms) . Biopolymers . 1997;41:495–509
  20. Lacroix E , Viguera AR , Serrano L . Elucidating the folding problem of alpha-helices (local motifs, long-range electrostatics, ionic-strength dependence and prediction of NMR parameters) . J Mol Biol . 1998;284:173–191
  21. Halangk J, Berg T, Puhl G, Mueller T, Nickel R, Kage A, et al. Keratin 8 Y54H and G62C mutations are not associated with liver disease . J Med Genet . 2004;41:e92
  22. Hesse M , Berg T , Wiedenmann B , Spengler U , Woitas RP , Magin TM . A frequent keratin 8 p.L227L polymorphism, but no point mutations in keratin 8 and 18 genes, in patients with various liver disorders . J Med Genet . 2004;41:e42
  23. Cavestro GM, Frulloni L, Nouvenne A, Neri TM, Calore B, Ferri B, et al. Association of keratin 8 gene mutation with chronic pancreatitis . Dig Liver Dis . 2003;35:416–420
  24. Owens DW, Wilson NJ, Hill AJ, Rugg EL, Porter RM, Hutcheson AM, et al. Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients . J Cell Sci . 2004;117:1989–1999
  25. Buning C, Halangk J, Dignass A, Ockenga J, Deindl P, Nickel R, et al. Keratin 8 Y54H and G62C mutations are not associated with inflammatory bowel disease . Dig Liver Dis . 2004;36:388–391
  26. Lee P , Gelbart T , West C , Halloran C , Beutler E . Seeking candidate mutations that affect iron homeostasis . Blood Cells Mol Dis . 2002;29:471–487
  27. Zhou Q , Ji X , Chen L , Greenberg HB , Lu SC , Omary MB . Keratin mutation primes mouse liver to oxidative injury . Hepatology . 2005;41:517–525
  28. Toivola DM , Ku NO , Resurreccion EZ , Nelson DR , Wright TL , Omary MB . Keratin 8 and 18 hyperphosphorylation is a marker of human liver disease progression . Hepatology . 2004;40:459–466
  29. Stumptner C , Omary MB , Fickert P , Denk H , Zatloukal K . Hepatocyte cytokeratins are hyperphosphorylated at multiple sites in human alcoholic hepatitis and in a mallory body mouse model . Am J Pathol . 2000;156:77–90

 Supported by VA Merit and National Institutes of Health (NIH) grant DK47918 awards (to M.B.O.), and NIH Digestive Disease Center grant DK56339. N.-O.K. is supported in part by a Veterans Administration Research Enhancement Award Program, and NIH DK56339 Pilot Award.

PII: S0016-5085(05)01353-3

doi: 10.1053/j.gastro.2005.06.065

Gastroenterology
Volume 129, Issue 3 , Pages 885-893 , September 2005

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