Abstract |
Keratins 8 and 18 (K8/18) are major constituents of Mallory bodies (MBs), which are hepatocyte cytoplasmic inclusions seen in several liver diseases. K18-null but not K8-null or heterozygous mice form MBs, which indicates that K8 is important for MB formation. Early stages in MB genesis include K8/18 hyperphosphorylation and overexpression. We used transgenic mice that overexpress K8, K18, or K8/18 to test the importance of K8 and/or K18 in MB formation. MBs were induced by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Livers of young K8 or K8/ K18 overexpressors had no histological abnormalities despite increased keratin protein and phosphorylation. In aging mice, only K8-overexpressing livers spontaneously developed small "pre-MB" aggregates. Only K8-overexpressing young mice are highly susceptible to MB formation after short-term DDC feeding. Thus, the K8 to K18 ratio, rather than K8/18 overexpression by itself, plays an essential role in MB formation. K8 overexpression is sufficient to form pre-MB and primes animals to accumulate MBs upon DDC challenge, which may help explain MB formation in human liver diseases.
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Authors | Ikuo Nakamichi, Diana M Toivola, Pavel Strnad, Sara A Michie, Robert G Oshima, Hélène Baribault, M Bishr Omary |
Journal | The Journal of cell biology
(J Cell Biol)
Vol. 171
Issue 6
Pg. 931-7
(Dec 19 2005)
ISSN: 0021-9525 [Print] United States |
PMID | 16365160
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- KRT18 protein, human
- Keratin-18
- Keratin-8
- Krt8 protein, mouse
- Mallory body protein, mouse
- Proteins
- RNA, Messenger
- Keratins
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Topics |
- Animals
- Gene Expression Regulation
(physiology)
- Hepatocytes
(ultrastructure)
- Humans
- Inclusion Bodies
(ultrastructure)
- Keratin-18
- Keratin-8
- Keratins
(metabolism)
- Liver
(enzymology, metabolism)
- Mice
- Mice, Transgenic
- Microscopy, Fluorescence
- Models, Biological
- Proteins
(metabolism)
- RNA, Messenger
(metabolism)
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