The involvement of Ran GTPase in lipopolysaccharide endotoxin-induced responses.
By functional cloning, we have established that Ran GTPase is involved in LPS-induced signal transduction. This has been accomplished by several functional comparisons of the two cDNAs, Lps(n)/Ran (or RanT/n) and Lps(d)/Ran (or RanC/d), which were isolated from cDNA libraries of LPS responder and hyporesponder mice, respectively. The letter n refers to the "normal" phenotype and the letter d refers to the "deficient" phenotype. Consistent with our previous results, more animal studies indicated that adenoviral transduction of RanC/d cDNA, but not RanT/n cDNA, into sensitive mice conferred significant resistance against endotoxin challenge. Thus the incorporation of RanC/d cDNA into gene therapy protocols as a therapeutic sequence remains very attractive. At steady state, hematopoietic cells transduced with RanC/d cDNA led to about a 10-fold increase in exogenous Ran protein compared with RanT/n cDNA. Furthermore, our cumulative data suggest that a slight elevation of Ran protein in B cells enhances LPS responsiveness, but the same elevation of Ran in macrophages does not. On the other hand, a high level of overexpression of Ran in both macrophages and B cells down-regulates LPS signal transduction. Thus LPS-induced signal transduction in macrophages and B cells is likely to occur via different signaling pathways.
Zhao
F
F
Department of Pathology and Laboratory Medicine, The Fels Institute, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Yuan
Q
Q
Sultzer
B M
BM
Chung
S W
SW
Wong
P M
PM
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D015723:Gene Library; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D015398:Signal Transduction / Q000276:immunology; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D020931:ran GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D020931:ran GTP-Binding Protein