Expression of mutant ubiquitin (UBB<sup>+1</sup>) and p62 in myotilinopathies and desminopathies

Olivé, Montse; Leeuwen, Fred W. van; Janué, Anna; Moreno, Dolores; Torrejón‐Escribano, Benjamín; Ferrer, Isidre

doi:10.1111/j.1365-2990.2007.00864.x

Cited by 57 publications

(49 citation statements)

References 42 publications

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“…Finally, ubiquitin, gelsolin and particularly myotilin expression is much more intense in myotilinopathy than desminopathy patients. 2,50,[111][112][113][114] Histological and immunohistochemical analysis of skeletal muscles in zaspopathy 115 reveal abnormalities very similar to those found in myotilinopathy. The hallmark of desminopathy, the granulofilamentous material, could also be present in myotilinopathy, zaspopathy and filaminopathy patients, but autophagic vacuoles, myofibrillar degeneration and accumulation of compacted and fragmented filaments and dense material seem to be more consistently found in myotilinopathy and zaspopathy.…”

Section: Differences and Similaritiesmentioning

confidence: 67%

“…The hallmark of desminopathy, the granulofilamentous material, could also be present in myotilinopathy, zaspopathy and filaminopathy patients, but autophagic vacuoles, myofibrillar degeneration and accumulation of compacted and fragmented filaments and dense material seem to be more consistently found in myotilinopathy and zaspopathy. [111][112][113][114][115] In addition, clusters of cytoplasmic 15-28 nm filaments have been observed in myotilinopathy. 114,116 In a subset of patients with mutations in SEPN1 gene, muscle biopsies showed distinctive circumscribed hyaline plaques resembling Mallory bodies known in hepatic disorders.…”

Section: Differences and Similaritiesmentioning

confidence: 99%

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Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

104

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Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations. The age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Typically, the illness presents with lower and later upper limb muscle weakness slowly spreading to involve truncal, neckflexor, facial and bulbar muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks, arrhythmias and chronic heart failure resulting in premature sudden death. Respiratory muscle weakness is a major complication in some patients. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing chimeric aggregates consisting of desmin and other cytoskeletal proteins. Various DES gene mutations: point mutations, an insertion, small in-frame deletions and a larger exon-skipping deletion, have been identified in desminopathy patients. The majority of these mutations are located in conserved alpha-helical segments, but additional mutations have recently been identified in the tail domain. Filament and network assembly studies indicate that most but not all disease-causing mutations make desmin assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. AlphaBcrystallin serves as a chaperone for desmin preventing its aggregation under various forms of stress; mutant CRYAB causes cardiac and skeletal myopathies identical to those resulting from DES mutations.

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Section: Differences and Similaritiesmentioning

confidence: 67%

Section: Differences and Similaritiesmentioning

confidence: 99%

Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

104

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“…As shown in Fig. 2g p62 (sequestosome 1) is a multifunctional signal adaptor that colocalizes with ubiquitinated protein aggregation in many neurodegenerative diseases and proteinopathies of the liver (17). As a link between LC3 and ubiquitinated substrates, p62 can be incorporated into the completed autophagosome and be degraded in autolysosomes (18).…”

Section: Western Blot Analysis Of Lc3 Lipidation (Lc3-ii) Is Regardedmentioning

confidence: 98%

Role of autophagy in resistance to oxaliplatin in hepatocellular carcinoma cells

Yang²,

Chen³

et al. 2011

Oncol Rep

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Abstract. In spite of an initially promising anti-tumor activity, oxaliplatin-based combinatorial treatments can eventually result in a tumor resistance response. In this study we aimed to understand the role of autophagy in HCC cell resistance to oxaliplatin and to discuss its potential therapeutic implication. We found that exposure to oxaliplatin induced a significant increase in LC3 lipidation and subsequent LC3 puncta formation. While the proliferation of HCC cells was inhibited upon oxaliplatin exposure, inhibition of autophagy by ATG7 interference and chloroquine pre-treatment further increased the sensitivity to chemotherapy. Meanwhile, the oxaliplatininduced apoptotic cell death was significantly enhanced. These results suggest that autophagy may function importantly in HepG2 cell resistance to oxaliplatin. Intriguingly, the resistance could be recovered apparently by inhibition of autophagy. This also points to the potential therapy for hepatoma by perturbing autophagy.

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“…protein is a multifunctional signal adaptor protein that can be incorporated into the completed autophagosome and degraded in autolysosomes (23). We used p62 as a surrogate marker to monitor autophagic flux.…”

Section: Changes In P62 Expression Following Acute I/h the P62mentioning

confidence: 99%

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

Yang

Chen

et al. 2012

Int J Oncol

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Abstract. Hepatocellular carcinoma (HCC) is the most common primary malignancy found in the liver. Autophagy is the intracellular bulk degradation process for long-lived proteins and dysfunctional organelles. In this study, we report that autophagy plays a role in HCC cell proliferation in response to ischemia-hypoxia (I/H) and reperfusion and discuss its potential therapeutic implications. By establishing a simulated model in cultured HepG2 (p53 wild-type) and Hep3B (p53 null) hepatoma cells in vitro, we found that exposure to I/H induced a significant increase in microtubule-associated protein 1 light chain 3 (LC3) lipidation and subsequent LC3 puncta formation. While the proliferation of HCC cells was stimulated upon acute I/H exposure compared to that of control, inhibition of autophagy by autophagy-related protein 7 interference abolished it. In addition, the steady-state levels of sequestosome 1 (p62) in both HepG2 and Hep3B cells were reduced following I/H exposure, supporting the notion that acute I/H induces autophagy. Intriguingly, the p62 level further decreased during reperfusion following I/H, accompanied by increased LC3 lipidation. The intracellular reactive oxygen species (ROS) accumulated during acute I/H exposure and persisted through reperfusion in both HepG2 and Hep3B cells and the ROS levels increased at a much faster rate during reperfusion than during I/H periods in both cells. Autophagy functions as a promoter for HCC cell survival during acute I/H and reperfusion and this also points to potential therapy for hepatoma by perturbing the acute I/H-reperfusionautophagy axis. IntroductionHepatocellular carcinoma (HCC) causes almost half a million deaths each year, making HCC the third most common cause of cancer-related mortality (1). Despite recent progress in diagnostic and therapeutic management, HCC prognosis remains poor (2). HCC is often diagnosed at an advanced stage when resection, transplantation, percutaneous and transarterial interventions are often of limited efficacy. Although sorafenib has demonstrated promising results in improving the survival and the time to progression in patients with advanced HCC, HCC is frequently resistant to conventional chemotherapy and radiotherapy (3).Ischemia-hypoxia (I/H) and reperfusion constitute key components of many pathological conditions associated with solid tumors. As the liver is a key metabolic organ in humans, the abnormal vasculature network, high interstitial pressure and high proliferation rate of HCC cells result in different types of hypoxia, such as transient hypoxia and chronic hypoxia (4). In response to I/H, the formation of tumor collateral vessels can induce subsequent reperfusion, resulting in oxidative stress (5). Consistent with the described scenario, HCC cells are reportedly more sensitive to I/H and reperfusion injury than normal liver tissue (6).Transcatheter arterial chemoembolization (TACE) has become one of the most widely used treatments for patients with HCC as a palliative measure (7). However, increased microves...

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Expression of mutant ubiquitin (UBB⁺¹) and p62 in myotilinopathies and desminopathies

Cited by 57 publications

References 42 publications

Intermediate Filament Diseases: Desminopathy

Intermediate Filament Diseases: Desminopathy

Role of autophagy in resistance to oxaliplatin in hepatocellular carcinoma cells

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

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Expression of mutant ubiquitin (UBB+1) and p62 in myotilinopathies and desminopathies

Cited by 57 publications

References 42 publications

Intermediate Filament Diseases: Desminopathy

Intermediate Filament Diseases: Desminopathy

Role of autophagy in resistance to oxaliplatin in hepatocellular carcinoma cells

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

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Expression of mutant ubiquitin (UBB⁺¹) and p62 in myotilinopathies and desminopathies