p62 is involved in the mechanism of Mallory body formation

Li, Nan; Wu, Yong; Bardag‐Gorce, Fawzia; Li, Jun; French, Barbara A.; Fu, Alan; Francis, Tricia; Vu, Jennifer; French, Samuel W.

doi:10.1016/j.yexmp.2004.06.003

Cited by 42 publications

(21 citation statements)

References 30 publications

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“…38 The following prerequisites are required for MB formation in vivo as well as in vitro 1,25,26 : (1) imbalance of the keratin 8 to keratin 18 ratio; (2) ubiquitination of keratin; (3) p62 with intact UBA domain for binding ubiquitinated keratin; and (4) overexpression of these components. The importance of p62 for MB formation is also emphasized by the studies of Nan et al, 36 using primary cultures of hepatocytes from drug-primed mice. These authors found that blocking p62 expression inhibited, whereas p62 overexpression increased, MB formation.…”

Section: Discussionmentioning

confidence: 99%

In vitroproduction 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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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…25,40,41 In this context, p62 may have a dualistic role by aggregating abnormal ubiquitinated proteins but also by shuttling them to the proteasomal and/or autophagosomal machineries. 39,42 The role of impaired K-related proteolysis in MDB formation is supported by our immunoblotting and immunofluorescence data showing persistence of K8 in hepatocytes of chronically intoxicated krt18 À/À mouse livers (Supplementary Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Genetic background effects of keratin 8 and 18 in a DDC-induced hepatotoxicity and Mallory-Denk body formation mouse model

Haybaeck

Stumptner

Thueringer

et al. 2012

Laboratory Investigation

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Keratin 8 (K8) and keratin 18 (K18) form the major hepatocyte cytoskeleton. We investigated the impact of genetic loss of either K8 or K18 on liver homeostasis under toxic stress with the hypothesis that K8 and K18 exert different functions. krt8À/À and krt18 À/À mice crossed into the same 129-ola genetic background were treated by acute and chronic administration of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). In acutely DDC-intoxicated mice, macrovesicular steatosis was more pronounced in krt8 À/À and krt18 À/À compared with wild-type (wt) animals. Mallory-Denk bodies (MDBs) appeared in krt18 À/À mice already at an early stage of intoxication in contrast to krt8 À/À mice that did not display MDB formation when fed with DDC. Keratin-deficient mice displayed significantly lower numbers of apoptotic hepatocytes than wt animals. krt8 À/À , krt18 À/À and control mice displayed comparable cell proliferation rates. Chronically DDC-intoxicated krt18 À/À and wt mice showed a similarly increased degree of steatohepatitis with hepatocyte ballooning and MDB formation. In krt8 À/À mice, steatosis was less, ballooning, and MDBs were absent. krt18 À/À mice developed MDBs whereas krt8 À/À mice on the same genetic background did not, highlighting the significance of different structural properties of keratins. They are independent of the genetic background as an intrinsic factor. By contrast, toxicity effects may depend on the genetic background. krt8À/À and krt18 À/À mice on the same genetic background show similar sensitivity to DDC intoxication and almost resemble wt animals regarding survival, degree of porphyria, liver-to-body weight ratio, serum bilirubin and liver enzyme levels. This stands in contrast to previous work where krt8 À/À and krt18 À/À mice on different genetic backgrounds were investigated.

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“…The excess K8, a superior TG2 substrate compared with K18, is not protected by its heterodimer K18, rendering it more accessible for crosslinking (96). Third, the presence of p62 - and likely its upregulation - is essential (97,98). Fourth, there must be several genetic modifiers, which remain to be defined, given the dramatic mouse strain difference in susceptibility to MDB formation (99).…”

Section: Figurementioning

confidence: 99%

Toward unraveling the complexity of simple epithelial keratins in human disease

Omary¹,

Ku²,

Strnad³

et al. 2009

J. Clin. Invest.

242

357

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Simple epithelial keratins (SEKs) are found primarily in single-layered simple epithelia and include keratin 7 (K7), K8, K18-K20, and K23. Genetically engineered mice that lack SEKs or overexpress mutant SEKs have helped illuminate several keratin functions and served as important disease models. Insight into the contribution of SEKs to human disease has indicated that K8 and K18 are the major constituents of Mallory-Denk bodies, hepatic inclusions associated with several liver diseases, and are essential for inclusion formation. Furthermore, mutations in the genes encoding K8, K18, and K19 predispose individuals to a variety of liver diseases. Hence, as we discuss here, the SEK cytoskeleton is involved in the orchestration of several important cellular functions and contributes to the pathogenesis of human liver disease.

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p62 is involved in the mechanism of Mallory body formation

Cited by 42 publications

References 30 publications

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

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

Genetic background effects of keratin 8 and 18 in a DDC-induced hepatotoxicity and Mallory-Denk body formation mouse model

Toward unraveling the complexity of simple epithelial keratins in human disease

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