Linked Life Data

11278678

Source:http://linkedlifedata.com/resource/pubmed/id/11278678

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
19
pubmed:dateCreated
2001-5-7
pubmed:abstractText
The Rho GTPase, Rac2, is expressed only in hematopoietic cell lineages, suggesting a specific cellular function in these cells. Genetic targeting studies in mice showed that Rac2 is an essential regulator of neutrophil chemotaxis, L-selectin capture and rolling, and superoxide production. Recently, a dominant negative mutation of Rac2, D57N, has been reported to be associated with a human phagocytic immunodeficiency. To understand further the cellular phenotypes associated with this D57N Rac2 mutant we examined its biochemical characteristics and functional effects when expressed in primary murine bone marrow cells. When compared with wild type (WT) Rac2, D57N Rac2 displayed approximately 10% GTP binding ability resulting from a markedly enhanced rate of GTP dissociation and did not respond to the guanine nucleotide exchange factors. These results suggest that D57N Rac2 may act in a dominant negative fashion in cells by sequestering endogenous guanine nucleotide exchange factors. When expressed in hematopoietic cells, D57N Rac2 reduced endogenous activities of not only Rac2, but also Rac1 and decreased cell expansion in vitro in the presence of growth factors due to increased cell apoptosis. Unexpectedly, D57N expression had no effect on proliferation. In contrast, expansion of cells transduced with WT Rac2 and a dominant active mutant, Q61L, was associated with significantly increased proliferation. Transplantation of transduced bone marrow cells into lethally irradiated recipients showed that the percentage of D57N-containing peripheral blood cells decreased markedly from 40% at 1 month to <5% by 3 months postinjection. Neutrophils derived in vitro from the transduced progenitor cells containing D57N demonstrated markedly impaired migration and O(2)(-) responses to formyl-methionyl-leucyl-phenylalanine, reflecting the same cellular phenotype in these differentiated cells as those described previously in patient cells. These data suggest that the phenotypic abnormalities associated with D57N Rac2 may involve not only neutrophil cellular functions, but also abnormal cell survival in other hematopoietic cells and that overexpression of Rac leads to increased proliferation of normal cells in vitro, whereas deficiency of Rac leads to increased apoptosis.
pubmed:grant
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
11
pubmed:volume
276
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
15929-38
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:11278678-Amino Acid Substitution, pubmed-meshheading:11278678-Animals, pubmed-meshheading:11278678-Bone Marrow Cells, pubmed-meshheading:11278678-Cell Division, pubmed-meshheading:11278678-Cell Line, pubmed-meshheading:11278678-Cell Survival, pubmed-meshheading:11278678-Cloning, Molecular, pubmed-meshheading:11278678-GTP Phosphohydrolases, pubmed-meshheading:11278678-Guanosine Diphosphate, pubmed-meshheading:11278678-Guanosine Triphosphate, pubmed-meshheading:11278678-Hematopoietic Stem Cell Transplantation, pubmed-meshheading:11278678-Hematopoietic Stem Cells, pubmed-meshheading:11278678-Humans, pubmed-meshheading:11278678-Immunologic Deficiency Syndromes, pubmed-meshheading:11278678-Mice, pubmed-meshheading:11278678-Mice, Knockout, pubmed-meshheading:11278678-N-Formylmethionine Leucyl-Phenylalanine, pubmed-meshheading:11278678-Neutrophils, pubmed-meshheading:11278678-Phagocytosis, pubmed-meshheading:11278678-Phenotype, pubmed-meshheading:11278678-Recombinant Proteins, pubmed-meshheading:11278678-Superoxides, pubmed-meshheading:11278678-Transfection, pubmed-meshheading:11278678-rac GTP-Binding Proteins
pubmed:year
2001
pubmed:articleTitle
Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency.
pubmed:affiliation
Howard Hughes Medical Institute and the Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.