Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours
Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours
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DOI：
10.1038/nature00848
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发表时间：
2002-06-20
期刊：
影响因子：
64.8
通讯作者：
Collard, JG
中科院分区：
文献类型：
--
作者：
Malliri, A;van der Kammen, RA;Collard, JG
Rho家族的蛋白质控制调节肌动蛋白细胞骨架和基因转录的信号传导途径（1，2）。体外研究表明Rho样GTP水解酶（GTP酶）参与细胞迁移（3-5）、细胞周期进展（6，7）和Ras诱导的病灶形成（8，9），表明这些GTP酶在体内肿瘤形成和进展中发挥作用。为了研究这一点，我们产生了缺乏Rac特异性激活剂Tiam 1（10-12）的小鼠，Tiam 1是一种T淋巴瘤侵袭和转移诱导蛋白。在这里，我们表明，这样的Tiam 1（-/-）小鼠对Ras诱导的皮肤肿瘤的发展具有抗性，这些肿瘤由7，12-二甲基苯并蒽引发，并由12-O-十四烷酰基佛波醇-13-乙酸酯促进。此外，Tiam 1（-/-）小鼠中产生的少数肿瘤比野生型小鼠中的肿瘤生长得慢得多。Tiam 1缺陷的原代胚胎成纤维细胞也对Ras（V12）诱导的病灶形成具有抗性。Tiam 1杂合子的分析表明，肿瘤的启动和促进依赖于Tiam 1基因剂量。Tiam 1缺陷与启动过程中的凋亡增加有关，与促进过程中的增殖受阻有关。虽然Tiam 1（-/-）小鼠的肿瘤数量很少，但进展为恶性肿瘤的比例更大，这表明Tiam 1缺陷促进了恶性转化。我们的研究确定了Rac激活剂Tiam 1作为Ras诱导肿瘤形成的不同方面的关键调节剂。
Proteins of the Rho family control signalling pathways that regulate the actin cytoskeleton and gene transcription(1,2). In vitro studies have implicated Rho-like GTP-hydrolysing enzymes (GTPases) in cell migration(3-5), cell-cycle progression(6,7), and Ras-induced focus formation 8,9, suggesting a role for these GTPases in the formation and progression of tumours in vivo. To study this, we have generated mice lacking the Rac-specific activator Tiam1(10-12), a T-lymphoma invasion and metastasis inducing protein. Here we show that such Tiam1(-/-) mice are resistant to the development of Ras-induced skin tumours initiated with 7,12-dimethylbenzanthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate. Moreover, the few tumours produced in Tiam1(-/-) mice grew much slower than did tumours in wild-type mice. Tiam1-deficient primary embryonic fibroblasts were also resistant to Ras(V12)-induced focus formation. Analysis of Tiam1 heterozygotes indicated that both tumour initiation and promotion were dependent on the Tiam1 gene dose. Tiam1 deficiency was associated with increased apoptosis during initiation, and with impeded proliferation during promotion. Although the number of tumours in Tiam1(-/-) mice was small, a greater proportion progressed to malignancy, suggesting that Tiam1 deficiency promotes malignant conversion. Our studies identify the Rac activator Tiam1 as a critical regulator of different aspects of Ras-induced tumour formation.