Pmc. Wong et al., Lps(d)/Ran of endotoxin-resistant C3H/HeJ mice is defective in mediating lipopolysaccharide endotoxin responses, P NAS US, 96(20), 1999, pp. 11543-11548
Citations number
48
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
C3H/HeJ inbred mice are defective in that they are highly resistant to endo
toxic shock as compared with normal responder mice. Their B cells and macro
phages do not respond significantly when exposed to lipopolysaccharide (LPS
), whereas cells from the responder mice do. Using a functional assay, we p
reviously isolated a cDNA, which encodes for Ran/TC4 GTPase. We now show th
at this gene is mutated in C3H/HeJ mice, which accounts for their resistanc
e to endotoxin stimulation. Sequence analysis of independent mutant Lps(d)/
Ran cDNAs isolated from splenic B cells of C3H/HeJ mice reveals a consisten
t single base substitution at position 870, where a thymidine is replaced w
ith a cytidine. In situ hybridization maps the Lpsd/Ran cDNA to mouse chrom
osome 4. By retroviral gene transfer, the wild-type Lps(n)/Ran cDNA but not
the mutant Lpsd/Ran cDNA can restore LPS responsiveness of C3H/HeJ cells,
adenoviral gene transfer in viva with the mutant Lpsd/Ran cDNA but not the
wild-type Lps(n)/Ran cDNA rescues endotoxin-sensitive mice from septic shoc
k Thus Lps/Ran is an important target for LPS-mediated signal transduction,
and the Lpsd/Ran gene may be useful as a therapeutic sequence in gene ther
apy for endotoxemia and septic shock.