scholarly journals Degradation of the Met tyrosine kinase receptor by the ubiquitin-proteasome pathway.

1997 ◽  
Vol 17 (2) ◽  
pp. 799-808 ◽  
Author(s):  
M Jeffers ◽  
G A Taylor ◽  
K M Weidner ◽  
S Omura ◽  
G F Vande Woude
Keyword(s):  
Tyrosine Kinase ◽  
Cellular Transformation ◽  
Kinase Domain ◽  
Tyrosine Kinase Receptor ◽  
Met Receptor ◽  
Ubiquitin Proteasome Pathway ◽  
Proteolytic Pathway ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway

The Met tyrosine kinase receptor is a widely expressed molecule which mediates pleiotropic cellular responses following activation by its ligand, hepatocyte growth factor/scatter factor (HGF/SF). In this communication we demonstrate that significant Met degradation is induced by HGF/SF and that this degradation can be blocked by lactacystin, an inhibitor of proteasome activity. We also show that Met is rapidly polyubiquitinated in response to ligand and that polyubiquitinated Met molecules, which are normally unstable, are stabilized by lactacystin. Both HGF/SF-induced degradation and polyubiquitination of Met were shown to be dependent on the receptor possessing intact tyrosine kinase activity. Finally, we found that a normally highly labile 55-kDa fragment of the Met receptor is stabilized by lactacystin and demonstrate that it represents a cell-associated remnant that is generated following the ligand-independent proteolytic cleavage of the Met receptor in its extracellular domain. This truncated Met molecule encompasses the kinase domain of the receptor and is itself tyrosine phosphorylated. We conclude that the ubiquitin-proteasome pathway plays a significant role in the degradation of the Met tyrosine kinase receptor as directed by ligand-dependent and -independent signals. We propose that this proteolytic pathway may be important for averting cellular transformation by desensitizing Met signaling following ligand stimulation and by eliminating potentially oncogenic fragments generated via extracellular cleavage of the Met receptor.

scholarly journals Cks1 is degraded via the ubiquitin-proteasome pathway in a cell cycle-dependent manner

2003 ◽  
Vol 8 (11) ◽  
pp. 889-896 ◽  
Author(s):  
Takayuki Hattori ◽  
Kyoko Kitagawa ◽  
Chiharu Uchida ◽  
Toshiaki Oda ◽  
Masatoshi Kitagawa
Keyword(s):  
Cell Cycle ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner

2000 ◽  
Vol 113 (23) ◽  
pp. 4363-4371 ◽  
Author(s):  
J. Zhao ◽  
T. Tenev ◽  
L.M. Martins ◽  
J. Downward ◽  
N.R. Lemoine
Keyword(s):  
Cell Cycle ◽  
Proteasome Inhibitors ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Apoptosis Protein ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

Survivin, a human inhibitor of apoptosis protein (IAP), plays an important role in both cell cycle regulation and inhibition of apoptosis. Survivin is expressed in cells during the G(2)/M phase of the cell cycle, followed by rapid decline of both mRNA and protein levels at the G(1) phase. It has been suggested that cell cycle-dependent expression of survivin is regulated at the transcriptional level. In this study we demonstrate involvement of the ubiquitin-proteasome pathway in post-translational regulation of survivin. Survivin is a short-lived protein with a half-life of about 30 minutes and proteasome inhibitors greatly stabilise survivin in vivo. Expression of the survivin gene under the control of the CMV promoter cannot block cell cycle-dependent degradation of the protein. Proteasome inhibitors can block survivin degradation during the G(1) phase and polyubiquitinated derivatives can be detected in vivo. Mutation of critical amino acid residues within the baculovirus IAP repeat (BIR) domain or truncation of the N terminus or the C terminus sensitises survivin to proteasome degradation. Together, these results indicate that the ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner and structural changes greatly destabilise the survivin protein.

scholarly journals High-Throughput Bioluminescence Screening of Ubiquitin-Proteasome Pathway Inhibitors from Chemical and Natural Sources

2006 ◽  
Vol 12 (1) ◽  
pp. 106-116 ◽  
Author(s):  
Frederic Ausseil ◽  
Arnaud Samson ◽  
Yannick Aussagues ◽  
Isabelle Vandenberghe ◽  
Laurent Creancier ◽  
...  
Keyword(s):  
Plant Extracts ◽  
Chemical Compounds ◽  
Protein Accumulation ◽  
Human Colon Cancer ◽  
Western Blot Assay ◽  
Screening Process ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway

To discover original inhibitors of the ubiquitin-proteasome pathway, the authors have developed a cell-based bioluminescent assay and used it to screen collections of plant extracts and chemical compounds. They first established a DLD-1 human colon cancer cell line that stably expresses a 4Ubiquitin-Luciferase (4Ub-Luc) reporter protein, efficiently targeted to the ubiquitinproteasome degradation pathway. The assay was then adapted to 96- and 384-well plate formats and calibrated with reference proteasome inhibitors. Assay robustness was carefully assessed, particularly cell toxicity, and the statistical Ź factor value was calculated to 0.83, demonstrating a good performance level of the assay. A total of 18,239 molecules and 15,744 plant extracts and fractions thereof were screened for their capacity to increase the luciferase activity in DLD-1 4Ub-Luc cells, and 21 molecules and 66 extracts inhibiting the ubiquitin-proteasome pathway were identified. The fractionation of an active methanol extract of Physalis angulata L. aerial parts was performed to isolate 2 secosteroids known as physalin B and C. In a cell-based Western blot assay, the ubiquitinated protein accumulation was confirmed after a physalin treatment confirming the accuracy of the screening process. The method reported here thus provides a robust approach to identify novel ubiquitin-proteasome pathway inhibitors in large collections of chemical compounds and natural products.

A new model of cancer cachexia: contribution of the ubiquitin-proteasome pathway

1999 ◽  
Vol 277 (2) ◽  
pp. E332-E341 ◽  
Author(s):  
Douglas D. Lazarus ◽  
Antonia T. Destree ◽  
Laureen M. Mazzola ◽  
Teresa A. McCormack ◽  
Lawrence R. Dick ◽  
...  
Keyword(s):  
Muscle Protein ◽  
Muscle Weight ◽  
New Model ◽  
Ubiquitin Proteasome Pathway ◽  
Colon 26 ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Conjugation ◽  
A Cell ◽  
Proteasome Pathway ◽  
Factor Α

A new model of cachexia is described in which muscle protein metabolism related to the ubiquitin-proteasome pathway was investigated. Cloning of the colon-26 tumor produced a cell line, termed R-1, which induced cytokine (noninterleukin-1β, interleukin-6 and tumor necrosis factor-α)-independent cachexia. Implantation of R-1 cells in mice elicited significant (20–30%) weight loss and decreased blood glucose by 70%, and adipose tissue levels declined by 95% and muscle weights decreased by 20–25%. Food intake was unaffected. The decrease in muscle weight reflected a decline in insoluble, but not soluble, muscle protein that was associated with a significant increase in net protein degradation. The rate of ubiquitin conjugation of proteins was significantly elevated in muscles of cachectic mice. Furthermore, the proteasome inhibitor lactacystin blocked the increase in protein breakdown but had no significant effect on proteolysis. Several markers of the ubiquitin-proteasome pathway, E214k mRNA and E214k protein and ubiquitin-protein conjugates, were not elevated. Future investigations with this new model should gain further insights into the mechanisms of cachexia and provide a background to evaluate novel and more efficacious therapies.

The Ubiquitin-Proteasome Pathway an Emerging Anticancer Strategy for Therapeutics: A Patent Analysis

2015 ◽  
Vol 10 (2) ◽  
pp. 201-213 ◽  
Author(s):  
Chakresh Jain ◽  
Shivam Arora ◽  
Aparna Khanna ◽  
Money Gupta ◽  
Gulshan Wadhwa ◽  
...  
Keyword(s):  
Patent Analysis ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

scholarly journals Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

2012 ◽  
Vol 117 (2) ◽  
pp. 329-338 ◽  
Author(s):  
Willem-Jan M. Schellekens ◽  
Hieronymus W. H. van Hees ◽  
Michiel Vaneker ◽  
Marianne Linkels ◽  
P. N. Richard Dekhuijzen ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Caspase 3 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Diaphragm Atrophy ◽  
Deficient Mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

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