Linked Life Data

18775730

Source:http://linkedlifedata.com/resource/pubmed/id/18775730

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2008-10-20
pubmed:abstractText
Deleted in Split hand/Split foot 1 (DSS1) was previously identified as a novel 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible gene with possible involvement in early event of mouse skin carcinogenesis. The mechanisms by which human DSS1 (HsDSS1) exerts its biological effects via regulation of the ubiquitin-proteasome system (UPS) are currently unknown. Here, we demonstrated that HsDSS1 regulates the human proteasome by associating with it in the cytosol and nucleus via the RPN3/S3 subunit of the 19S regulatory particle (RP). Molecular anatomy of HsDSS1 revealed an RPN3/S3-interacting motif (R3IM), located at amino acid residues 15 to 21 of the NH(2) terminus. Importantly, negative charges of the R3IM motif were demonstrated to be required for proteasome interaction and binding to poly-ubiquitinated substrates. Indeed, the R3IM motif of HsDSS1 protein alone was sufficient to replace the ability of intact HsDSS1 protein to pull down proteasome complexes and protein substrates with high-molecular mass ubiquitin conjugates. Interestingly, this interaction is highly conserved throughout evolution from humans to nematodes. Functional study, lowering the levels of the endogenous HsDSS1 using siRNA, indicates that the R3IM/proteasome complex binds and targets p53 for ubiquitin-mediated degradation via gankyrin-MDM2/HDM2 pathway. Most significantly, this work indicates that the R3IM motif of HsDSS1, in conjunction with the complexes of 19S RP and 20S core particle (CP), regulates proteasome interaction through RPN3/S3 molecule, and utilizes a specific subset of poly-ubiquitinated p53 as a substrate.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/26S proteasome non-ATPase..., http://linkedlifedata.com/resource/pubmed/chemical/MDM2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/PSMD10 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex, http://linkedlifedata.com/resource/pubmed/chemical/Protein Subunits, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-mdm2, http://linkedlifedata.com/resource/pubmed/chemical/SHFM1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/TP53 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Protein p53, http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1089-8638
pubmed:author
pubmed:issnType
Electronic
pubmed:day
14
pubmed:volume
383
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
693-712
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.
pubmed:affiliation
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. wei2@niehs.nih.gov
pubmed:publicationType
Journal Article