Mutation of a major keratin phosphorylation site predisposes to hepatotoxic injury in transgenic mice

Nam-on Ku, Sara A. Michie, Roy M. Soetikno, Evelyn Z. Resurreccion, Rosemary L. Broome, M. Bishr Omary

Research output: Contribution to journalArticle

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Abstract

Simple epithelia express keratins 8 (K8) and 18 (K18) as their major intermediate filament (IF) proteins. One important physiologic function of K8/18 is to protect hepatocytes from drug-induced liver injury. Although the mechanism of this protection is unknown, marked K8/18 hyperphosphorylation occurs in association with a variety of cell stresses and during mitosis. This increase in keratin phosphorylation involves multiple sites including human K18 serine-(ser)52, which is a major K18 phosphorylation site. We studied the significance of keratin hyperphosphorylation and focused on K18 ser52 by generating transgenic mice that over-express a human genomic K18 ser52→ala mutant (S52A) and compared them with mice that overexpress, at similar levels, wild-type (WT) human K18. Abrogation of K18 ser52 phosphorylation did not affect filament organization after partial hepatectomy nor the ability of mouse livers to regenerate. However, exposure of S52A-expressing mice to the hepatotoxins, griseofulvin or microcystin, which are associated with K18 ser52 and other keratin phosphorylation changes, resulted in more dramatic hepatotoxicity as compared with WT K18- expressing mice. Our results demonstrate that K18 ser52 phosphorylation plays a physiologic role in protecting hepatocytes from stress-induced liver injury. Since hepatotoxins are associated with increased keratin phosphorylation at multiple sites, it is likely that unique sites aside from K18 ser52, and phosphorylation sites on other IF proteins, also participate in protection from cell stress.

Original languageEnglish
Pages (from-to)2023-2032
Number of pages10
JournalJournal of Cell Biology
Volume143
Issue number7
DOIs
Publication statusPublished - 1998 Dec 28

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Keratins
Transgenic Mice
Phosphorylation
Mutation
Keratin-8
Keratin-18
Wounds and Injuries
Intermediate Filament Proteins
Hepatocytes
Griseofulvin
Chemical and Drug Induced Liver Injury
Cytoprotection
Liver
Hepatectomy
Mitosis
Serine
Epithelium

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Ku, N., Michie, S. A., Soetikno, R. M., Resurreccion, E. Z., Broome, R. L., & Bishr Omary, M. (1998). Mutation of a major keratin phosphorylation site predisposes to hepatotoxic injury in transgenic mice. Journal of Cell Biology, 143(7), 2023-2032. https://doi.org/10.1083/jcb.143.7.2023
Ku, Nam-on ; Michie, Sara A. ; Soetikno, Roy M. ; Resurreccion, Evelyn Z. ; Broome, Rosemary L. ; Bishr Omary, M. / Mutation of a major keratin phosphorylation site predisposes to hepatotoxic injury in transgenic mice. In: Journal of Cell Biology. 1998 ; Vol. 143, No. 7. pp. 2023-2032.
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abstract = "Simple epithelia express keratins 8 (K8) and 18 (K18) as their major intermediate filament (IF) proteins. One important physiologic function of K8/18 is to protect hepatocytes from drug-induced liver injury. Although the mechanism of this protection is unknown, marked K8/18 hyperphosphorylation occurs in association with a variety of cell stresses and during mitosis. This increase in keratin phosphorylation involves multiple sites including human K18 serine-(ser)52, which is a major K18 phosphorylation site. We studied the significance of keratin hyperphosphorylation and focused on K18 ser52 by generating transgenic mice that over-express a human genomic K18 ser52→ala mutant (S52A) and compared them with mice that overexpress, at similar levels, wild-type (WT) human K18. Abrogation of K18 ser52 phosphorylation did not affect filament organization after partial hepatectomy nor the ability of mouse livers to regenerate. However, exposure of S52A-expressing mice to the hepatotoxins, griseofulvin or microcystin, which are associated with K18 ser52 and other keratin phosphorylation changes, resulted in more dramatic hepatotoxicity as compared with WT K18- expressing mice. Our results demonstrate that K18 ser52 phosphorylation plays a physiologic role in protecting hepatocytes from stress-induced liver injury. Since hepatotoxins are associated with increased keratin phosphorylation at multiple sites, it is likely that unique sites aside from K18 ser52, and phosphorylation sites on other IF proteins, also participate in protection from cell stress.",
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Ku, N, Michie, SA, Soetikno, RM, Resurreccion, EZ, Broome, RL & Bishr Omary, M 1998, 'Mutation of a major keratin phosphorylation site predisposes to hepatotoxic injury in transgenic mice', Journal of Cell Biology, vol. 143, no. 7, pp. 2023-2032. https://doi.org/10.1083/jcb.143.7.2023

Mutation of a major keratin phosphorylation site predisposes to hepatotoxic injury in transgenic mice. / Ku, Nam-on; Michie, Sara A.; Soetikno, Roy M.; Resurreccion, Evelyn Z.; Broome, Rosemary L.; Bishr Omary, M.

In: Journal of Cell Biology, Vol. 143, No. 7, 28.12.1998, p. 2023-2032.

Research output: Contribution to journalArticle

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T1 - Mutation of a major keratin phosphorylation site predisposes to hepatotoxic injury in transgenic mice

AU - Ku, Nam-on

AU - Michie, Sara A.

AU - Soetikno, Roy M.

AU - Resurreccion, Evelyn Z.

AU - Broome, Rosemary L.

AU - Bishr Omary, M.

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N2 - Simple epithelia express keratins 8 (K8) and 18 (K18) as their major intermediate filament (IF) proteins. One important physiologic function of K8/18 is to protect hepatocytes from drug-induced liver injury. Although the mechanism of this protection is unknown, marked K8/18 hyperphosphorylation occurs in association with a variety of cell stresses and during mitosis. This increase in keratin phosphorylation involves multiple sites including human K18 serine-(ser)52, which is a major K18 phosphorylation site. We studied the significance of keratin hyperphosphorylation and focused on K18 ser52 by generating transgenic mice that over-express a human genomic K18 ser52→ala mutant (S52A) and compared them with mice that overexpress, at similar levels, wild-type (WT) human K18. Abrogation of K18 ser52 phosphorylation did not affect filament organization after partial hepatectomy nor the ability of mouse livers to regenerate. However, exposure of S52A-expressing mice to the hepatotoxins, griseofulvin or microcystin, which are associated with K18 ser52 and other keratin phosphorylation changes, resulted in more dramatic hepatotoxicity as compared with WT K18- expressing mice. Our results demonstrate that K18 ser52 phosphorylation plays a physiologic role in protecting hepatocytes from stress-induced liver injury. Since hepatotoxins are associated with increased keratin phosphorylation at multiple sites, it is likely that unique sites aside from K18 ser52, and phosphorylation sites on other IF proteins, also participate in protection from cell stress.

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