Dolado Ignacio, Swat Aneta, Ajenjo Nuria, De Vita Gabriella, Cuadrado Ana, Nebreda Angel R
CNIO (Spanish National Cancer Center), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Cancer Cell. 2007 Feb;11(2):191-205. doi: 10.1016/j.ccr.2006.12.013.
p38alpha is a stress-activated protein kinase that negatively regulates malignant transformation induced by oncogenic H-Ras, although the mechanisms involved are not fully understood. Here, we show that p38alpha is not a general inhibitor of oncogenic signaling, but that it specifically modulates transformation induced by oncogenes that produce reactive oxygen species (ROS). This inhibitory effect is due to the ROS-induced activation of p38alpha early in the process of transformation, which induces apoptosis and prevents the accumulation of ROS and their carcinogenic effects. Accordingly, highly tumorigenic cancer cell lines have developed a mechanism to uncouple p38alpha activation from ROS production. Our results indicate that oxidative stress sensing plays a key role in the inhibition of tumor initiation by p38alpha.
p38α是一种应激激活的蛋白激酶，它对致癌性H-Ras诱导的恶性转化起负调控作用，尽管其中涉及的机制尚未完全明确。在此，我们表明p38α并非致癌信号的一般抑制剂，而是特异性地调节由产生活性氧（ROS）的致癌基因所诱导的转化。这种抑制作用是由于在转化过程早期ROS诱导p38α激活，进而诱导细胞凋亡并阻止ROS的积累及其致癌作用。因此，高致瘤性癌细胞系已形成一种机制，使p38α激活与ROS产生解偶联。我们的结果表明，氧化应激感应在p38α对肿瘤起始的抑制中起关键作用。
