Mechanisms of Mallory Body Formation Induced by Okadaic Acid in Drug-Primed Mice

Yuan, Q X; Nagao, Yasuyuki; Gaal, Karl; Hu, Bing; French, Samuel W.

doi:10.1006/exmp.1998.2231

Cited by 32 publications

(28 citation statements)

References 30 publications

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“…Journal of Cell Science 115 (21) Orthovanadate-induced cytokeratin filament remodeling is similar to that occurring during mitosis but is profoundly different from that mediated by okadaic acid The effect of various modulators of phosphorylation on the dynamics and organization of the CKF cytoskeleton has been the subject of many studies (Baribault et al, 1989;Eckert and Yeagle, 1990;Cadrin et al, 1992;Falconer and Yeung, 1992;Ohta et al, 1992;Deery, 1993;Kasahara et al, 1993;Yatsunami et al, 1993;Baricault et al, 1994;Blankson et al, 1995;Toivola et al, 1997;Toivola et al, 1998;Yuan et al, 1998;Feng et al, 1999;Paramio, 1999;Sanhai et al, 1999;Negron and Eckert, 2000;Strnad et al, 2001). One of the best examined drugs in this context is the serine/threonine phosphatase inhibitor okadaic acid, which induces complete disruption of the CKF system and results in formation of granular aggregates (Kasahara et al, 1993;Yatsunami et al, 1993;Chou and Omary, 1994;Blankson et al, 1995;Strnad et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…For example, during chronic liver disease Mallory bodies are formed, which contain large amounts of hyperphosphorylated CK polypeptides (Franke et al, 1979;Cadrin and Martinoli, 1995;Stumptner et al, 2000). In this case, phoshorylation itself may be the cause of aggregation (Yuan et al, 1998), possibly by preventing ubiquitin-dependent degradation (Ku and Omary, 2000;Coulombe and Omary, 2002). Granular aggregates are also a hallmark of various genodermatoses (Anton-Lamprecht, 1983;Coulombe et al, 1991;Cadrin and Martinoli, 1995;Kobayashi et al, 1999).…”

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confidence: 99%

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Induction of rapid and reversible cytokeratin filament network remodeling by inhibition of tyrosine phosphatases

Strnad

Windoffer

Leube

2002

Journal of Cell Science

105

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The cytokeratin filament network is intrinsically dynamic, continuously exchanging subunits over its entire surface, while conferring structural stability on epithelial cells. However, it is not known how cytokeratin filaments are remodeled in situations where the network is temporarily and spatially restricted. Using the tyrosine phosphatase inhibitor orthovanadate we observed rapid and reversible restructuring in living cells, which may provide the basis for such dynamics. By examining cells stably expressing fluorescent cytokeratin chimeras, we found that cytokeratin filaments were broken down and then formed into granular aggregates within a few minutes of orthovanadate addition. After drug removal, gradual reincorporation of granules into the filament network was observed for aggregates that were either part of residual filaments or stayed in close apposition to remaining filaments. Even when cytokeratin filaments were no longer detectable, granules with low mobility were still able to reestablish a cytokeratin filament network. This process took less than 30 minutes and occurred at multiple foci throughout the cytoplasm without apparent correlation to alterations in the actin- and tubulin-based systems. Interestingly, the short-lived and rather small orthovanadate-induced cytokeratin granules contained the cytoskeletal crosslinker plectin but lacked the cytokeratin-solubilising 14-3-3 proteins. By contrast, the long-lived and larger cytokeratin aggregates generated after treatment with the serine/threonine phosphatase inhibitor okadaic acid were negative for plectin but positive for 14-3-3 proteins. Taken together, our observations in living orthovanadate-treated interphase cells revealed modes of cytokeratin remodeling that qualify as basic mechanisms capable of rapidly adapting the cytokeratin filament cytoskeleton to specific requirements.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Induction of rapid and reversible cytokeratin filament network remodeling by inhibition of tyrosine phosphatases

Strnad

Windoffer

Leube

2002

Journal of Cell Science

105

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“…It is known that protein phosphatases are important regulators of steady-state cytokeratin phosphorylation. 20,40,60,64 Furthermore, different turnover rates were identified for the various phosphorylation sites on CK8 and CK18. 48 In contrast to CK8, which showed a higher steady-state phosphorylation in a variety of situations, including chronic intoxication of mice with GF or stimulation of PKC in cultured hepatocytes, CK18 had a lower steady state phosphorylation level because of rapid dephosphorylation by protein phosphatases.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a possible association of cytokeratin hyperphosphorylation with the formation of MBs in hepatocytes, a hallmark of AH, was suggested by in vitro and animal studies performed by our own group and others. [17][18][19][20] AH follows chronic alcohol abuse and occurs in 20 to 40% of heavy drinkers. Although reversible at the beginning, most cases of AH progress to irreversible cirrhosis.…”

mentioning

confidence: 99%

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Stumptner¹,

Omary²,

Fickert³

et al. 2000

The American Journal of Pathology

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Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies , termed Mallory bodies (MBs).Cytokeratins are members of the large family of intermediate filament (IF) cytoskeletal proteins, which are normally expressed in a tissue-specific manner and assembled as cytoplasmic filamentous arrays. Neurofilaments, ␣-internexin, desmin, vimentin, glial filaments, and the nuclear lamins 1,2 also belong to the IF family. The diverse cell biological functions of IFs are still poorly understood. However, a diversity of human diseases is associated with severe alterations of IFs. A common pathological feature of many IF-related diseases is the accumulation of intracytoplasmic inclusions consisting of modified IF proteins, for example in neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Lewy body dementia 3-6 ; in neuromuscular disorders (eg, spheroid body myositis 7 ); and the formation of Mallory bodies (MBs) in alcoholic hepatitis (AH) and other liver disorders (eg, non-alcoholic steatohepatitis, Wilson's disease, primary biliary cirrhosis, Indian childhood cirrhosis, hepatocellular neoplasms 8 -11 ). Although the underlying pathogenetic mechanisms are as yet unclear, posttranslational modifications of IF proteins, such as phosphorylation, limited proteolysis, and crosslinking, may play a major role. For example, the presence of hyperphosphorylated neurofilament epitopes in some neuronal inclusion bodies 12-15 and of abnormally phosphorylated desmin in muscle fibers 16 were reported. Furthermore, a possible association of cytokeratin hyperphosphorylation with the formation of MBs in hepatocytes, a hallmark of AH, was suggested by in vitro and animal studies performed by our own group and others. [17][18][19][20] AH follows chronic alcohol abuse and occurs in 20 to 40% of heavy drinkers. Although reversible at the beginning, most cases of AH progress to irreversible cirrhosis. Besides the amount of alcohol ingested per day, a variety of other factors such as dietary habits, genetic factors influencing alcohol metabolism, viral infections, and additional toxins or drugs seem to determine the extent of liver damage. Classical morphological features of AH are liver cell ballooning and necrosis, inflammation, steatosis, and the formation of cytokeratin-containing MBs, which is associated with severe derangement (ie, diminution or even loss) of the hepatocyte cytokeratin IF network. 8 -11,22-26 Diverse animal models have been generated to study in more detail and under defined conditions mechanisms involved in the pathogenesis of this alcoholic liver disease. Experimental long-term intoxication of mice with Supported by the grants of the Austrian Science Foundation S7401-MOB (to K. Z.) and 7628-MED (to H. D.) and by a U.S. Veterans Affairs Merit and Career Development Award (to M. B. O.).

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“…In epithelial cells, the main constituents are keratins 8 and 18 (K8 and K18), typically in a hyperphosphorylated state (30)(31)(32). In fact, hyperphosphorylated keratin IFs are plentiful in aggresomes of other cells, possibly even initiating their formation (31,33). Signaling pathways, such as src, AKT, p38, and ERK, likely mediate this process (33)(34)(35).…”

Section: Keratin Ifs and Aggresomesmentioning

confidence: 99%

The Role of the Ubiquitin Proteasome Pathway in Keratin Intermediate Filament Protein Degradation

Rogel

Jaitovich²,

Ridge

2010

Proceedings of the American Thoracic Society

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Mechanisms of Mallory Body Formation Induced by Okadaic Acid in Drug-Primed Mice

Cited by 32 publications

References 30 publications

Induction of rapid and reversible cytokeratin filament network remodeling by inhibition of tyrosine phosphatases

Induction of rapid and reversible cytokeratin filament network remodeling by inhibition of tyrosine phosphatases

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

The Role of the Ubiquitin Proteasome Pathway in Keratin Intermediate Filament Protein Degradation

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