Linked Life Data

11704659

Source:http://linkedlifedata.com/resource/pubmed/id/11704659

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2002-1-14
pubmed:abstractText
The fifth component of the COP9 signalosome complex, Jab1/CSN5, directly binds to and induces specific down-regulation of the cyclin-dependent kinase inhibitor p27 (p27(Kip1)). Nuclear-cytoplasmic translocation plays an important role because leptomycin B (LMB), a chemical inhibitor of CRM1-dependent nuclear export, prevents p27 degradation mediated by Jab1/CSN5. Here we show that Jab1/CSN5 functions as an adaptor between p27 and CRM1 to induce nuclear export and subsequent degradation. Jab1/CSN5, but not p27, contains a typical leucine-rich nuclear export signal (NES) sequence conserved among different species, through which CRM1 bound to Jab1/CSN5 in an LMB-sensitive manner. Alteration of conserved leucine residues to alanine within Jab1/CSN5-NES abolished the interaction with CRM1 in vitro and impaired LMB-sensitive nuclear export and the ability to induce p27 breakdown in cultured cells. A Jab1/CSN5 truncation mutant lacking NES reversed p27 down-regulation induced by the full-length Jab1/CSN5, indicating that this mutant functions as a dominant negative (DN-Jab1). Introduction of DN-Jab1 into proliferating fibroblasts increased the level of p27 protein, thereby inducing growth arrest of the cells. Random mutagenesis analysis revealed that specific aspartic acid, leucine, and asparagine residues contained in the Jab1/CSN5-binding domain of p27 were required for interaction with Jab1/CSN5 and for down-regulation of p27. Glycerol gradient and cell fractionation experiments showed that at least two different forms of Jab1/CSN5-containing complexes existed within the cell. One is the conventional 450-kDa COP9 signalosome (CSN) complex located in the nucleus, and the other is much smaller (around 100-kDa), containing only a subset of CSN components (CSN4-8 but not CSN1-3), and mainly located in the cytoplasm. Treatment of cells with LMB greatly reduced the level of the smaller complex, suggesting that it originated from the CSN complex by nuclear export. Besides Jab1/CSN5, CSN3, -6, -7, and -8 were capable of inducing p27 down-regulation, when ectopically expressed. These results indicate that cytoplasmic shuttling regulated by Jab1/CSN5 and other CSN components may be a new pathway to control the intracellular abundance of the key cell cycle regulator.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
18
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2302-10
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:11704659-3T3 Cells, pubmed-meshheading:11704659-Amino Acid Motifs, pubmed-meshheading:11704659-Amino Acid Sequence, pubmed-meshheading:11704659-Animals, pubmed-meshheading:11704659-COS Cells, pubmed-meshheading:11704659-Cell Cycle Proteins, pubmed-meshheading:11704659-Cell Nucleus, pubmed-meshheading:11704659-Cyclin-Dependent Kinase Inhibitor p27, pubmed-meshheading:11704659-Cytoplasm, pubmed-meshheading:11704659-DNA-Binding Proteins, pubmed-meshheading:11704659-Hydrolysis, pubmed-meshheading:11704659-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:11704659-Mice, pubmed-meshheading:11704659-Molecular Sequence Data, pubmed-meshheading:11704659-Peptide Hydrolases, pubmed-meshheading:11704659-Protein Binding, pubmed-meshheading:11704659-Protein Transport, pubmed-meshheading:11704659-Sequence Homology, Amino Acid, pubmed-meshheading:11704659-Signal Transduction, pubmed-meshheading:11704659-Transcription Factors, pubmed-meshheading:11704659-Tumor Suppressor Proteins
pubmed:year
2002
pubmed:articleTitle
The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/CSN5 and the COP9 signalosome complex.
pubmed:affiliation
Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't