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The involvement of Ran GTPase in lipopolysaccharide endotoxin-induced responses

Department of Pathology and Laboratory Medicine, Fels Institute, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

Quan Yuan

Department of Pathology and Laboratory Medicine, Fels Institute, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

Barnet M. Sultzer

StemCell Therapeutics, King of Prussia, Pennsylvania, USA

Siu-Wah Chung

Department of Pathology and Laboratory Medicine, Fels Institute, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

Peter M.C. Wong

Department of Pathology and Laboratory Medicine, Fels Institute, Temple University School of Medicine, Philadelphia, Pennsylvania, USA, Petermcw{at}aol.com

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, Lpsⁿ/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.

Journal of Endotoxin Research, Vol. 7, No. 1, 53-56 (2001)
DOI: 10.1177/09680519010070010901


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