Keratin mutation primes mouse liver to oxidative injury†

Zhou, Qin; Ji, Xuhuai; Chen, Lixin; Greenberg, Harry B.; Lu, Shelly C.; Omary, M. Bishr

doi:10.1002/hep.20578

Cited by 39 publications

(32 citation statements)

References 49 publications

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“…Ku reported that mutations of CK8 and CK18 are risk factors for developing human liver diseases [20]. CK8/18 mutations may trigger oxidative injury in hepatocytes [32], and such an overexpression of CK8/18 is maintained in human hepatocellular carcinomas [2]. Thus, CK8 phosphorylation and CK8/18 mutations are probably responsible for the induction of CK8/18-positive liver proliferative lesions.…”

Section: Discussionmentioning

confidence: 99%

Cytokeratin 8/18 is a Useful Immunohistochemical Marker for Hepatocellular Proliferative Lesions in Mice

et al. 2010

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ABSTRACT. In order to clarify whether cytokeratin (CK) 8/18 is a useful immunohistochemical marker for hepatocellular proliferative lesions in mice, partially hepatectomized male ICR mice were given 0.6% piperonyl butoxide (PBO) for 8 (Experiment I) or 25 weeks (Experiment II) after N-diethylnitrosamine (DEN) initiation treatment, and the livers were subjected to histological examinations on hematoxylin and eosin (HE) stained sections, CK8/18 immunohistochemistry and gamma-glutamyl transpeptidase (GGT) histochemistry. In Experiment I, the multiplicity of hepatocellular foci in paraffin-embedded sections which were observed in HE-stained sections and positive for CK8/18 was 10.17 and 18.50, respectively, while that of hepatocellular foci in frozen sections which were observed in HEstained sections and positive/negative for GGT was 6.17 and 8.17, respectively. In Experiment II, the total multiplicity of hepatocellular foci in paraffin-embedded sections which were observed in HE-stained sections and positive/negative for CK8/18 was 4.47 and 23.17, respectively, while that of hepatocellular foci in frozen sections which were observed in HE-stained sections and positive/negative for GGT was 2.50 and 3.50, respectively. Most of the hepatocellular adenomas and carcinomas observed in HE-stained sections were positive for CK8/18, but some of the adenomas were negative for CK8/18. These findings indicate that more hepatocellular proliferative lesions can be detected in CK8/18 immunohistochemistry in addition to those observed in HE-stained sections, and suggest that CK8/ 18 may become a useful immunohistochemical marker for detecting hepatocellular proliferative lesions in mice. The rat liver medium-term bioassay system first established by Ito et al. [14] has been repeatedly used for the detection of carcinogenic or tumor promoting potential of chemical substances and has a great advantage due to reproducibility and reliability for generation of data within 8 weeks [8]. For assessment of promoting effects of the test chemicals, glutathione S-transferase placental form (GST-P)-positive foci are used as the primary endpoint. Moreover, since production of GST-P positive foci has been closely correlated with the actual tumor yields [11,21], they are regarded as the reliable preneoplastic lesion in rats. However, it is generally recognized that this immunohistochemical marker is not reactive for liver preneoplastic and neoplastic lesions of mice. It has been shown that gammaglutamyl transpeptidase (GGT) play a role in multistage hepatocarcinogenesis and the enhanced expression of this enzyme is observed in preneoplastic altered hepatocellular foci, hepatocellular adenomas, and hepatocellular carcinomas in rats and mice [13]. Therefore, GGT is used as a histochemical marker for these proliferative lesions in mice. However, this histochemical staining of GGT is not suitable for routine histopathological examinations, because frozen sections are necessary for this staining. In addition, there is a disadvantage that almost all th...

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Section: Discussionmentioning

confidence: 99%

Cytokeratin 8/18 is a Useful Immunohistochemical Marker for Hepatocellular Proliferative Lesions in Mice

et al. 2010

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“…Moreover, keratin mutations prime hepatocytes to oxidative injury and may thus predispose patients to liver cirrhosis. 44 …”

Section: Discussionmentioning

confidence: 99%

In vitro production of Mallory bodies and intracellular hyaline bodies: The central role of sequestosome 1 / p62

et al. 2007

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M allory bodies (MBs) and intracellular hyaline bodies (IHBs) are hepatocellular inclusions that may occur in a diversity of chronic liver disorders. 1,2 They differ in their light and electron microscopic appearance and chemical composition but share sequestosome 1/p62 (p62) as a major component. [1][2][3][4] Whereas MBs contain in addition abnormal keratins, ubiquitin, and heat shock proteins, keratins are lacking in classical IHBs. 1,4 P62 is a multifunctional protein 5,6 with several structural motifs that determine its various functions: the SH2 domain binds the tyrosine kinase p56 lck in a phosphotyrosine-independent manner, an acidic interaction domain associates with the atypical protein kinase C and mediates the role of p62 as adapter in tumor necrosis factor alpha-initiated, interleukin-1-initiated, and nerve growth factor-initiated signal transduction, and a ZZ-type zinc finger binds the receptor interactive protein involved in tumor necrosis factor-induced apoptosis. Moreover, p62 contains a binding site for the tumor necrosis factor receptor-associated factor 6, which is an E3 ubiquitin ligase, two PEST (regions rich in proline, glutamate, serine, and threonine) sequences, and the ubiquitin-association (UBA) domain. [5][6][7] We have recently described the simultaneous occurrence of MBs and IHBs in neoplastic (hepatocellular carcinoma) and non-neoplastic (idiopathic copper toxicosis) hepatocytes, and of "hybrid" inclusions consisting of both Abbreviations: cDNA, complementary deoxyribonucleic acid; DDC,3, Ig, immunoglobulin; IHB, intracellular hyaline body; MB, Mallory body; p62, sequestosome 1/p62; UBA,

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“…The increased susceptibility of livers from K8-null mice, K18-null mice or mice with mutant K8 or K18 to injury is reflected by their enhanced susceptibility to undergo hepatocyte apoptosis. This might be related to redistribution of Fas cell surface receptors (Gilbert et al, 2001); decreased threshold to oxidative injury (Zhou et al, 2005); and the importance of keratins as a cytoprotective buffer by serving as a 'phosphate sponge' towards stress-activated kinases (Ku and Omary, 2006).…”

Section: Introductionmentioning

confidence: 99%

Keratins modulate the shape and function of hepatocyte mitochondria: a mechanism for protection from apoptosis

Guo

Looi

Toivola

et al. 2009

Journal of Cell Science

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Absence or mutation of keratins 8 (K8) or 18 (K18) cause predisposition to liver injury and apoptosis. We assessed the mechanisms of hepatocyte keratin-mediated cytoprotection by comparing the protein expression profiles of livers from wild-type and K8-null mice using two-dimensional differential-in-gel-electrophoresis (2D-DIGE) and mass spectrometry. Prominent among the alterations were those of mitochondrial proteins, which were confirmed using 2D-DIGE of purified mitochondria. Ultrastructural analysis showed that mitochondria of livers that lack or have disrupted keratins are significantly smaller than mitochondria of wild-type livers. Immunofluorescence staining showed irregular distribution of mitochondria in keratin-absent or keratin-mutant livers. K8-null livers have decreased ATP content; and K8-null mitochondria have less cytochrome c, increased release of cytochrome c after exposure to Ca2+ and oxidative stimulation, and a higher sensitivity to Ca2+-induced permeability transition. Therefore, keratins play a direct or indirect role in regulating the shape and function of mitochondria. The effects of keratin mutation on mitochondria are likely to contribute to hepatocyte predisposition to apoptosis and oxidative injury, and to play a pathogenic role in keratin-mutation-related human liver disease.

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Keratin mutation primes mouse liver to oxidative injury†

Cited by 39 publications

References 49 publications

Cytokeratin 8/18 is a Useful Immunohistochemical Marker for Hepatocellular Proliferative Lesions in Mice

Cytokeratin 8/18 is a Useful Immunohistochemical Marker for Hepatocellular Proliferative Lesions in Mice

In vitro production of Mallory bodies and intracellular hyaline bodies: The central role of sequestosome 1 / p62

Keratins modulate the shape and function of hepatocyte mitochondria: a mechanism for protection from apoptosis

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