Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells
Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells
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DOI：
10.1158/0008-5472.can-05-4629
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Kotani, Hidehito
中科院分区：
文献类型：
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作者：
Mizuarai, Shinji;Yamanaka, Kazunori;Kotani, Hidehito
已知肿瘤抑制基因p53通过反激活各种野生型（WT） p53调控基因诱导G(1)-S和G(2)-M细胞周期阻滞和凋亡。在超过一半的人类癌症中检测到p53突变失活，剥夺了p53蛋白的肿瘤抑制功能。最近的研究表明，突变型p53为肿瘤细胞提供了功能获得特性，如加速细胞增殖、增加转移和细胞凋亡抵抗。然而，p53突变导致致瘤性升高的机制仍有待阐明。在本研究中，我们发现GEF-H1是RhoA的鸟嘌呤交换因子- h1，通过诱导p53蛋白突变激活转录，从而加速肿瘤细胞的增殖。建立表达诱导型p53突变体（V157F、R175H和R248Q）的骨肉瘤U2OS细胞系，分析各细胞系的表达谱，检测p53突变体特异性诱导的基因。我们发现GEF-H1是三个突变体显著诱导其表达的共识基因之一。在32个癌细胞系中，GEF-H1表达水平与p53状态密切相关，GEFH1诱导可激活RhoA。此外，突变型p53细胞的生长依赖于GEF-H1的表达，而WT型p53细胞则不依赖于GEF-H1的表达。这些结果表明，增加的GEF-H1表达有助于与p53突变相关的肿瘤进展表型。
The tumor suppressor gene p53 is known to induce G(1)-S and G(2)-M Cell cycle arrest and apoptosis by transactivating various wild-type (WT) p53 regulatory genes. Mutational inactivation of p53 is detected in more than half of human cancers, depriving the p53 protein of its tumor-suppressive functions. Recent studies have shown that mutant p53 provides tumor cells with gain-of-function properties, such as accelerated cell proliferation, increased metastasis, and apoptosis resistance. However, the mechanism underlying the elevated tumorigenicity by p53 mutation remains to be elucidated. In the present study, we showed that GEF-H1, a guanine exchange factor-H1 for RhoA, is transcriptionally activated by the induction of mutant p53 proteins, thereby accelerating tumor cell proliferation. Osteosarcoma U2OS cell lines, which express inducible p53 mutants (V157F, R175H, and R248Q), were established, and the expression profiles of each cell line were then analyzed to detect genes specifically induced by mutant p53. We identified GEF-H1 as one of the consensus genes whose expression was significantly induced by the three mutants. The GEF-H1 expression level strongly correlated with p53 status in a panel of 32 cancer cell lines, and GEFH1 induction caused activation of RhoA. Furthermore, growth of mutant p53 cells was dependent on GEF-H1 expression, whereas that of WT p53 cells was not. These results suggest that increased GEF-H1 expression contributes to the tumor progression phenotype associated with the p53 mutation.