Linked Life Data

17671184

Source:http://linkedlifedata.com/resource/pubmed/id/17671184

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
2007-8-2
pubmed:abstractText
Cellular responses to gamma-irradiation exposure are controlled by phosphatidylinositol 3-kinase-related kinases (PIKK) in the nucleus, and in addition, cytosolic PIKKs may have a role in such responses. Here, we show that the expression of tripeptidyl-peptidase II (TPPII), a high molecular weight cytosolic peptidase, required PIKK signaling and that TPPII was rapidly translocated into the nucleus of gamma-irradiated cells. These events were dependent on mammalian target of rapamycin, a cytosolic/mitochondrial PIKK that is activated by gamma-irradiation. Lymphoma cells with inhibited expression of TPPII failed to efficiently stabilize p53 and had reduced ability to arrest proliferation in response to gamma-irradiation. We observed that TPPII contains a BRCA COOH-terminal-like motif, contained within sequences of several proteins involved in DNA damage signaling pathways, and this motif was important for nuclear translocation of TPPII and stabilization of p53. Novel tripeptide-based inhibitors of TPPII caused complete in vivo tumor regression in mice in response to relatively low doses of gamma-irradiation (3-4 Gy/wk). This was observed with established mouse and human tumors of diverse tissue backgrounds, with no tumor regrowth after cancellation of treatment. These TPPII inhibitors had minor effects on tumor growth as single agent and had low cellular toxicity. Our data indicated that TPPII connects signaling by cytosolic/mitochondrial and nuclear PIKK-dependent pathways and that TPPII can be targeted for inhibition of tumor therapy resistance.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
67
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7165-74
pubmed:dateRevised
2010-12-30
pubmed:meshHeading
pubmed-meshheading:17671184-Amino Acid Sequence, pubmed-meshheading:17671184-Aminopeptidases, pubmed-meshheading:17671184-Animals, pubmed-meshheading:17671184-DNA Damage, pubmed-meshheading:17671184-Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, pubmed-meshheading:17671184-Enzyme Inhibitors, pubmed-meshheading:17671184-Flow Cytometry, pubmed-meshheading:17671184-Gamma Rays, pubmed-meshheading:17671184-Humans, pubmed-meshheading:17671184-Immunoenzyme Techniques, pubmed-meshheading:17671184-Lymphoma, pubmed-meshheading:17671184-Mice, pubmed-meshheading:17671184-Mice, Inbred C57BL, pubmed-meshheading:17671184-Molecular Sequence Data, pubmed-meshheading:17671184-Phosphatidylinositol 3-Kinases, pubmed-meshheading:17671184-Plasmids, pubmed-meshheading:17671184-Protein-Serine-Threonine Kinases, pubmed-meshheading:17671184-RNA, Small Interfering, pubmed-meshheading:17671184-Radiation Tolerance, pubmed-meshheading:17671184-Serine Endopeptidases, pubmed-meshheading:17671184-Signal Transduction, pubmed-meshheading:17671184-Transfection, pubmed-meshheading:17671184-Tumor Cells, Cultured
pubmed:year
2007
pubmed:articleTitle
Tripeptidyl-peptidase II controls DNA damage responses and in vivo gamma-irradiation resistance of tumors.
pubmed:affiliation
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital-Huddinge.
pubmed:publicationType
Journal Article, Retracted Publication, Research Support, Non-U.S. Gov't