Lps(d)/Ran of endotoxin-resistant C3H/HeJ mice is defective in mediating lipopolysaccharide endotoxin responses.
Lps(d)/Ran of endotoxin-resistant C3H/HeJ mice is defective in mediating lipopolysaccharide endotoxin responses.
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DOI：
10.1073/pnas.96.20.11543
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发表时间：
1999-09
影响因子：
11.1
通讯作者：
P. Wong;A. Kang;H. Chen;Q. Yuan;P. Fan;B. M. Sultzer;Y. Kan;S. Chung
中科院分区：
文献类型：
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作者：
P. Wong;A. Kang;H. Chen;Q. Yuan;P. Fan;B. M. Sultzer;Y. Kan;S. Chung
C3 H/HeJ近交系小鼠的缺陷在于，与正常应答小鼠相比，它们对内毒素休克具有高度抗性。当暴露于脂多糖（LPS）时，它们的B细胞和巨噬细胞没有显著反应，而来自应答小鼠的细胞则有反应。使用功能性测定，我们先前分离了编码Ran/TC 4 GT3的cDNA。我们现在表明，该基因在C3 H/HeJ小鼠中发生突变，这说明了它们对内毒素刺激的抵抗力。从C3 H/HeJ小鼠脾B细胞分离的独立突变型LPS（d）/Ran cDNA的序列分析揭示了在位置870处一致的单碱基替换，其中胸苷被胞苷替换。原位杂交将Lps（d）/Ran cDNA定位于小鼠4号染色体。通过逆转录病毒基因转移，野生型Lps（n）/Ran cDNA能恢复C3 H/HeJ细胞对LPS的反应性，而突变型Lps（d）/Ran cDNA则不能。用突变型LPS（d）/Ran cDNA而非野生型LPS（n）/Ran cDNA进行的腺病毒基因体内转移拯救了内毒素敏感小鼠免于感染性休克。因此，Lps/Ran是LPS介导的信号转导的重要靶点，并且Lps（d）/Ran基因可能用作内毒素血症和感染性休克的基因治疗的治疗序列。
C3H/HeJ inbred mice are defective in that they are highly resistant to endotoxic shock as compared with normal responder mice. Their B cells and macrophages do not respond significantly when exposed to lipopolysaccharide (LPS), whereas cells from the responder mice do. Using a functional assay, we previously isolated a cDNA, which encodes for Ran/TC4 GTPase. We now show that this gene is mutated in C3H/HeJ mice, which accounts for their resistance to endotoxin stimulation. Sequence analysis of independent mutant Lps(d)/Ran cDNAs isolated from splenic B cells of C3H/HeJ mice reveals a consistent single base substitution at position 870, where a thymidine is replaced with a cytidine. In situ hybridization maps the Lps(d)/Ran cDNA to mouse chromosome 4. By retroviral gene transfer, the wild-type Lps(n)/Ran cDNA but not the mutant Lps(d)/Ran cDNA can restore LPS responsiveness of C3H/HeJ cells. Adenoviral gene transfer in vivo with the mutant Lps(d)/Ran cDNA but not the wild-type Lps(n)/Ran cDNA rescues endotoxin-sensitive mice from septic shock. Thus Lps/Ran is an important target for LPS-mediated signal transduction, and the Lps(d)/Ran gene may be useful as a therapeutic sequence in gene therapy for endotoxemia and septic shock.