Disturbances in hepatic cell-cycle regulation in mice with assembly-deficient keratins 8/18

Toivola, Diana M.; Nieminen, Mikko; Hesse, Michael; He, Tao; Baribault, Hélène; Magin, Thomas M.; Omary, M. Bishr; Eriksson, John E.

doi:10.1053/jhep.2001.29374

Cited by 73 publications

(51 citation statements)

References 47 publications

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“…Untreated K8-null and K18-null mice have normal-appearing exocrine pancreata apart from rare areas with abnormal structures that we have described earlier 23 Table 3B). After 14 days, the survivor K8-null and all the other mice had lost their acini and the tissue was replaced by ducts, fat and inflammation (Figure 2e-h and Table 3B).…”

Section: Dramatic Resistance and Recovery From Cvb4-p Virus Infectionsupporting

confidence: 66%

Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

Toivola¹,

Ostrowski²,

Baribault³

et al. 2009

CHC

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Keratins 8 and 18 (K8/K18) are the two major intermediate filament proteins in hepatocytes and pancreatic acinar cells. Acinar cell keratins are organized as cytoplasmic and apicolateral filaments. An important role of hepatocyte K8/K18 is to maintain cellular integrity, while this cytoprotective function of K8/K18 is not evident in the pancreas since keratin-deficient mice cope well with pancreatitis models. To further study the roles of keratins in the exocrine pancreas, we used coxsackievirus B4-models, CVB4-V and CVB4-P, to induce severe acute/chronic pancreatitis and acute pancreatitis, respectively, in K8-null (which lack acinar keratins) and K18-null (which lack cytoplasmic keratins) mice. Despite similar virus titers in all mice, CVB4-V resulted in 40% mortality of the K8-null mice 14 days post-infection compared to no lethality of WT and K18-null mice. In contrast, K8-null mice were far less susceptible to CVB4-P-induced damage as determined by histology and serology analysis, and they recover faster than WT and K18-null mice. After CVB4 virus infection, keratins aggregated during acinar degranulation, and K8/K18 site-specific phosphorylation was observed during degranulation and recovery. Hence, keratins significantly affect CVB4 virulence, positively or negatively, depending on the virus subtype and keratin makeup, in a virus replication-independent manner.

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Section: Dramatic Resistance and Recovery From Cvb4-p Virus Infectionsupporting

confidence: 66%

Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

Toivola¹,

Ostrowski²,

Baribault³

et al. 2009

CHC

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“…Notably, we found that both vimentin negative MCF-7 cells and vimentin positive HeLa and Panc-1 cells fail to target desmoplakin at cell borders. The role of keratins in the maintenance of desmosomes is also supported by findings of a careful histological characterisation of liver lesions in both K8 and K18 null mice (Toivola et al, 2001). Livers of keratin null mice showed large areas that were devoid of both desmoplakin and filamentous actin staining (Toivola et al, 2001).…”

Section: Periplakin Participates In Re-organisation Of Keratin Intermmentioning

confidence: 90%

“…The role of keratins in the maintenance of desmosomes is also supported by findings of a careful histological characterisation of liver lesions in both K8 and K18 null mice (Toivola et al, 2001). Livers of keratin null mice showed large areas that were devoid of both desmoplakin and filamentous actin staining (Toivola et al, 2001). One possible reason for mistargeting of desmoplakin in the absence of keratins could be altered function of plakophilins in the recruitment of desmoplakin.…”

Section: Periplakin Participates In Re-organisation Of Keratin Intermmentioning

confidence: 93%

Periplakin-dependent re-organisation of keratin cytoskeleton and loss of collective migration in keratin-8-downregulated epithelial sheets

Long

Boczonadi

McInroy

et al. 2006

Journal of Cell Science

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Collective migration of epithelial sheets requires maintenance of cell-cell junctions and co-ordination of the movement of the migrating front. We have investigated the role of keratin intermediate filaments and periplakin, a cytoskeletal linker protein, in the migration of simple epithelial cells. Scratch wounding induces bundling of keratins into a cable of tightly packed filaments adjacent to the free wound edge. Keratin re-organisation is preceded by a re-distribution of periplakin away from the free wound edge. Periplakin participates with dynamic changes in the keratin cytoskeleton via its C-terminal linker domain that co-localises with okadaic-acid-treated keratin granules. Stable expression of the periplakin C-terminal domain increases keratin bundling and Ser431 keratin phosphorylation at wound edge resulting in a delay in wound closure. Ablation of periplakin by siRNA inhibits keratin cable formation and impairs wound closure. Knockdown of keratin 8 with siRNA results in (1) a loss of desmoplakin localisation at cell borders, (2) a failure of MCF-7 epithelial sheets to migrate as a collective unit and (3) accelerated wound closure in vimentin-positive HeLa and Panc-1 cell lines. Thus, keratin 8 is required for the maintenance of epithelial integrity during migration and periplakin participates in the re-organisation of keratins in migrating cells.

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“…45 In addition, absence of K8/K18 proteins as a consequence of K8 gene ablation in mice results in alterations in cell cycle regulation. 46 Also, cell lines expressing epidermal keratin mutants that cause epidermolysis bullosa simplex manifest an accentuated stress-activated protein kinase response compared with cells that express their WT counterparts. 47 Although the details of how keratin mutations influence gene transcription has yet to be investigated, apoptosis is generally a downstream consequence of oxidative injury.…”

Section: Discussionmentioning

confidence: 99%

Keratin mutation primes mouse liver to oxidative injury†

Zhou

Chen

et al. 2005

Hepatology

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Mutation of the cytoskeletal intermediate filament proteins keratin 8 and keratin 18 (K8/K18) is associated with cirrhosis in humans, whereas transgenic mice that overexpress K18 Arg893 Cys (R89C) have significant predisposition to liver injury. To study the mechanism of keratinassociated predisposition to liver injury, we used mouse microarrays to examine genetic changes associated with hepatocyte keratin mutation and assessed the consequences of such changes. Liver gene expression was compared in R89C versus nontransgenic or wild-type K18-overexpressing mice. Microarray-defined genetic changes were confirmed by quantitative polymerase chain reaction. Nineteen genes had a more than two-fold altered expression (nine downregulated, 10 upregulated). Upregulated genes in keratin-mutant hepatocytes included the oxidative metabolism genes cytochrome P450, S-adenosylhomocysteine (SAH) hydrolase, cysteine sulfinic acid decarboxylase, and oxidation-reduction pathway genes. Downregulated genes included fatty acid binding protein 5, cyclin D1, and some signaling molecules. Several methionine metabolism-related and glutathione synthetic pathway intermediates, including S-adenosylmethionine (SAMe) and SAH, were modulated in R89C versus control mice. R89C livers had higher lipid and protein oxidation by-products as reflected by increased malondialdehyde and oxidized albumin. In conclusion, K18 point mutation in transgenic mice modulates several hepatocyte oxidative stress-related genes and leads to lipid and protein oxidative by-products. Mutationassociated decreases in SAH and SAMe could compromise needed cysteine availability to generate glutathione during oxidative stress. Hence keratin mutations may prime hepatocytes to oxidative injury, which provides a new potential mechanism for how keratin mutations may predispose patients to cirrhosis. (HEPATOLOGY 2005;41:517-525.)

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Disturbances in hepatic cell-cycle regulation in mice with assembly-deficient keratins 8/18

Cited by 73 publications

References 47 publications

Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

Periplakin-dependent re-organisation of keratin cytoskeleton and loss of collective migration in keratin-8-downregulated epithelial sheets

Keratin mutation primes mouse liver to oxidative injury†

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