LRRC4, a putative tumor suppressor gene, requires a functional leucine-rich repeat cassette domain to inhibit proliferation of glioma cells in vitro by modulating the extracellular signal-regulated kinase/protein kinase B/nuclear factor-κB pathway
LRRC4, a putative tumor suppressor gene, requires a functional leucine-rich repeat cassette domain to inhibit proliferation of glioma cells in vitro by modulating the extracellular signal-regulated kinase/protein kinase B/nuclear factor-κB pathway
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DOI：
10.1091/mbc.e05-11-1082
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发表时间：
2006-08-01
影响因子：
3.3
通讯作者：
Li, Guiyuan
中科院分区：
文献类型：
--
作者：
Wu, Minghua;Huang, Chen;Li, Guiyuan
我们以前已经报道过LRRC4基因，它包含一个保守的富含亮氨酸重复序列(LRR)盒和一个免疫球蛋白(Ig)IgC2结构域，在体外和体内都与胶质瘤抑制有关。本研究提供的证据表明，LRRC4在高级别胶质瘤中的明显缺失直接导致了肿瘤分级的增加。U251细胞中LRRC4基因的缺失是由染色体7q32-ter纯合性缺失引起的。研究还发现，LRRC4需要一个具有功能的LRR盒结构域来抑制U251细胞的增殖。在LRR盒结构域中，发现核心LRR的第三个LRR基序对LRRC4的功能是不可或缺的。LRRC4的抑制作用伴随着PERK、PACKT、pNF-kappa Bp65、信号转导和转录激活蛋白-3(STAT3)、突变型P53的表达降低，而c-jun NH2末端激酶(JNK)2和p-c-jun的表达增加，提示LRRC4通过调节细胞外信号调节蛋白(ERK)/Akt/NF-kappa Bp65、STAT3和JNK2/c-jun途径抑制U251细胞的增殖。综上所述，LRRC4可能是一种新的抑癌基因候选基因。因此，LRRC4功能缺失可能是脑胶质瘤发生发展过程中的重要事件。
We have previously reported that the LRRC4 gene, which contains a conserved leucine-rich repeat (LRR) cassette and an immunoglobulin (Ig) IgC2 domain, is associated with glioma suppression both in vitro and in vivo. The present study provides evidence that the conspicuous absence of LRRC4 in high-grade gliomas directly contributes to the increasing tumor grade. The loss of LRRC4 in U251 cells is caused by the loss of homozygosity at chromosome 7q32-ter. It was also found that LRRC4 requires a functional LRR cassette domain to suppress U251 cell proliferation. In the LRR cassette domain, the third LRR motif of the core LRR is found to be indispensable for the function of LRRC4. The inhibitory effect of LRRC4 is accompanied by a decrease in the expression of pERK, pAkt, pNF-kappa Bp65, signal transducer and activator of transcription protein-3 (STAT3), and mutant p53, and an increase in the expression of c-Jun NH2-terminal kinase (JNK)2 and p-c-Jun, suggesting that LRRC4 plays a major role in suppressing U251 cell proliferation by regulating the extracellular signal-regulated kinase (ERK)/Akt/NF-kappa Bp65, STAT3, and JNK2/c-jun pathways. In conclusion, LRRC4 may act as a novel candidate of tumor suppressor gene. Therefore, the loss of LRRC4 function may be an important event in the progression of gliomas.