Linked Life Data

17244621

Source:http://linkedlifedata.com/resource/pubmed/id/17244621

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
18
pubmed:dateCreated
2007-4-30
pubmed:abstractText
p53 is activated genetically by a set of kinases that are components of the calcium calmodulin kinase superfamily, including CHK2, AMP kinase, and DAPK-1. In dissecting the mechanism of DAPK-1 control, a novel mutation (N1347S) was identified in the death domain of DAPK-1. The N1347S mutation prevented the death domain module binding stably to ERK in vitro and in vivo. Gel filtration demonstrated that the N1347S mutation disrupted the higher order oligomeric nature of the purified recombinant death domain miniprotein. Accordingly, the N1347S death domain module is defective in vivo in the formation of high molecular weight oligomeric intermediates after cross-linking with ethylene glycol bis(succinimidylsuccinate). Full-length DAPK-1 protein harboring a N1347S mutation in the death domain was also defective in binding to ERK in cells and was defective in formation of an ethylene glycol bis(succinimidylsuccinate)-cross-linked intermediate in vivo. Full-length DAPK-1 encoding the N1347S mutation was attenuated in tumor necrosis factor receptor-induced apoptosis. However, the N1347S mutation strikingly prevented ERK:DAPK-1-dependent apoptosis as defined by poly(ADP-ribose) polymerase cleavage, Annexin V staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling imaging. Significant penetrance of the N1347S allele was identified in normal genomic DNA indicating the mutation is germ line, not tumor derived. The frequency observed in genomic DNA was from 37 to 45% for homozygous wild-type, 41 to 47% for heterozygotes, and 12 to 15% for homozygous mutant. These data highlight a naturally occurring DAPK-1 mutation that alters the oligomeric structure of the death domain, de-stabilizes DAPK-1 binding to ERK, and prevents ERK:DAPK-1-dependent apoptosis.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
4
pubmed:volume
282
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
13791-803
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:17244621-Adolescent, pubmed-meshheading:17244621-Adult, pubmed-meshheading:17244621-Aged, pubmed-meshheading:17244621-Aged, 80 and over, pubmed-meshheading:17244621-Alleles, pubmed-meshheading:17244621-Annexin A5, pubmed-meshheading:17244621-Apoptosis, pubmed-meshheading:17244621-Apoptosis Regulatory Proteins, pubmed-meshheading:17244621-Calcium-Calmodulin-Dependent Protein Kinases, pubmed-meshheading:17244621-DNA Fragmentation, pubmed-meshheading:17244621-Extracellular Signal-Regulated MAP Kinases, pubmed-meshheading:17244621-Female, pubmed-meshheading:17244621-Genome, Human, pubmed-meshheading:17244621-Germ-Line Mutation, pubmed-meshheading:17244621-Humans, pubmed-meshheading:17244621-Male, pubmed-meshheading:17244621-Middle Aged, pubmed-meshheading:17244621-Mutation, Missense, pubmed-meshheading:17244621-Neoplasms, pubmed-meshheading:17244621-Penetrance, pubmed-meshheading:17244621-Poly(ADP-ribose) Polymerases, pubmed-meshheading:17244621-Protein Binding, pubmed-meshheading:17244621-Protein Structure, Tertiary, pubmed-meshheading:17244621-Receptors, Tumor Necrosis Factor, pubmed-meshheading:17244621-Recombinant Proteins
pubmed:year
2007
pubmed:articleTitle
A germ line mutation in the death domain of DAPK-1 inactivates ERK-induced apoptosis.
pubmed:affiliation
Cancer Research UK p53 Signal Transduction Group, University of Edinburgh, South Crewe Road, Edinburgh EH4 2XR.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't