Linked Life Data

19609631

Source:http://linkedlifedata.com/resource/pubmed/id/19609631

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2009-12-24
pubmed:abstractText
The ubiquitin-dependent proteasome system (UPS) is the major pathway responsible for selective nuclear and cytoplasmic protein degradation. Bortezomib, a boronic acid dipeptide, is a reversible 20S proteasome inhibitor used as novel anticancer drug, particularly in the treatment of multiple myeloma and certain lymphomas. Bortezomib-induced peripheral neuropathy (BIPN) is a widely recognized dose-limiting neurotoxicity of this proteasome inhibitor, which causes a significant negative impact on the quality of life. The pathogenic mechanisms underlying bortezomib neurotoxicity are little known. In this study a rat was used as our animal model to investigate the bortezomib-induced nuclear changes in dorsal root ganglia (DRG) neurons. Our results indicate that this neuronal population is an important target of bortezomib neurotoxicity. Nuclear changes include accumulation of ubiquitin-protein conjugates, reduction of transcriptional activity, and nuclear retention of poly(A) RNAs in numerous spherical or ring-shaped dense granules. They also contained the RNA-binding proteins PABPN1 (poly(A) binding protein nuclear 1) and Sam68, but lacked the mRNA nuclear export factors REF and Y14. At the cytoplasmic level, most neurons exhibited chromatolysis, supporting the inhibition of mRNA translation. Our results indicate that bortezomib interferes with transcription, nuclear processing and transport, and cytoplasmic translation of mRNAs in DRG neurons. They also support that this neuronal dysfunction is an essential pathogenic mechanism in the BIPN, which is characterized by sensory impairment including sensory ataxia.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1476-3524
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
167-78
pubmed:meshHeading
pubmed-meshheading:19609631-Adaptor Proteins, Signal Transducing, pubmed-meshheading:19609631-Animals, pubmed-meshheading:19609631-Boronic Acids, pubmed-meshheading:19609631-Cell Nucleus, pubmed-meshheading:19609631-Ganglia, Spinal, pubmed-meshheading:19609631-Gene Expression Regulation, pubmed-meshheading:19609631-Male, pubmed-meshheading:19609631-Microscopy, Electron, Transmission, pubmed-meshheading:19609631-Poly(A)-Binding Protein II, pubmed-meshheading:19609631-Protease Inhibitors, pubmed-meshheading:19609631-Proteasome Endopeptidase Complex, pubmed-meshheading:19609631-Pyrazines, pubmed-meshheading:19609631-RNA, Messenger, pubmed-meshheading:19609631-Rats, pubmed-meshheading:19609631-Rats, Sprague-Dawley, pubmed-meshheading:19609631-Sensory Receptor Cells, pubmed-meshheading:19609631-Time Factors, pubmed-meshheading:19609631-Ubiquitin, pubmed-meshheading:19609631-Uridine
pubmed:year
2010
pubmed:articleTitle
Bortezomib induces the formation of nuclear poly(A) RNA granules enriched in Sam68 and PABPN1 in sensory ganglia neurons.
pubmed:affiliation
Department of Anatomy and Cell Biology and Centro de Investigación Biomédica en Red sobre Enferemedades Neurodegenerativas (CIBERNED), Faculty of Medicine, University of Cantabria, Avd. Cardenal Herrera Oria s/n, Santander, Spain.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't