An identity crisis for fps/fes: oncogene or tumor suppressor?
An identity crisis for fps/fes: oncogene or tumor suppressor?
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fps/fes 的身份危机：癌基因还是抑癌基因？
作者：
W. Sangrar;Ralph A Zirgnibl;Yan Gao;W. Muller;Z. Jia;P. Greer
FPS/Fes蛋白是蛋白酪氨酸激酶家族中最早被确定为显性作用癌蛋白的成员之一。加入逆转录病毒的Gag序列或其他实验诱导的突变激活了FPS/Fes的潜在转化潜力。然而，直到最近才在人类肿瘤中发现fps/fes的激活突变，当时对一组结直肠癌的突变分析发现，编码fps/fes激动域的序列中有四个体细胞突变。在这里，我们报告了生化和理论结构分析，证明其中三个突变导致FPS/FES的失活，而不是激活，而第四个突变降低了体内的活性。这些结果不符合fps/fes激活体细胞突变的经典显性致癌作用，而是提出了灭活fps/fes突变可能促进体内肿瘤进展的可能性。与此一致，我们观察到，在乳腺癌的小鼠模型中，肿瘤的发病较早发生在靶向为空或激酶失活的fps/fes突变的小鼠中。此外，fps/fes转基因在靶向fps/fes缺失小鼠中恢复了正常的肿瘤发病动力学。这些数据表明，FPS/FES在上皮细胞中具有一种新的和意想不到的肿瘤抑制作用。
Fps/Fes proteins were among the first members of the protein tyrosine kinase family to be characterized as dominant-acting oncoproteins. Addition of retroviral GAG sequences or other experimentally induced mutations activated the latent transforming potential of Fps/Fes. However, activating mutations in fps/fes had not been found in human tumors until recently, when mutational analysis of a panel of colorectal cancers identified four somatic mutations in sequences encoding the Fps/Fes kinase domain. Here, we report biochemical and theoretical structural analysis demonstrating that three of these mutations result in inactivation, not activation, of Fps/Fes, whereas the fourth mutation compromised in vivo activity. These results did not concur with a classic dominant-acting oncogenic role for fps/fes involving activating somatic mutations but instead raised the possibility that inactivating fps/fes mutations might promote tumor progression in vivo. Consistent with this, we observed that tumor onset in a mouse model of breast epithelial cancer occurred earlier in mice targeted with either null or kinase-inactivating fps/fes mutations. Furthermore, a fps/fes transgene restored normal tumor onset kinetics in targeted fps/fes null mice. These data suggest a novel and unexpected tumor suppressor role for Fps/Fes in epithelial cells.