Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01609, USA.
Oncogene. 2010 Mar 4;29(9):1280-92. doi: 10.1038/onc.2009.428. Epub 2009 Nov 23.
One of the pivotal functions of endogenous tumor suppression is to oppose aberrant cell survival, but the molecular requirements of this process are not completely understood. Here, we show that caspase 2, a death effector with largely unknown functions, represses transcription of the survivin gene, a general regulator of cell division and cytoprotection in tumors. This pathway involves caspase 2 proteolytic cleavage of the nuclear factor kappaB (NFkappaB) activator, RIP1. In turn, loss of RIP1 abolishes transcription of NFkappaB target genes, including survivin, resulting in deregulated mitotic transitions, enhanced apoptosis and suppression of tumorigenicity in vivo. Therefore, caspase 2 functions as an endogenous inhibitor of NFkappaB-dependent cell survival and this mechanism may contribute to tumor suppression in humans.
内源性肿瘤抑制的一个关键功能是对抗异常细胞存活，但这一过程的分子要求尚不完全清楚。在这里，我们表明，半胱天冬酶 2（一种具有很大未知功能的死亡效应物）抑制了生存素基因的转录，生存素是肿瘤中细胞分裂和细胞保护的一般调节剂。该途径涉及半胱天冬酶 2 对半胱天冬酶依赖性核因子 κB（NFκB）激活物 RIP1 的蛋白水解切割。反过来，RIP1 的缺失会使 NFκB 靶基因，包括生存素的转录失活，导致有丝分裂过渡失调、凋亡增强，并抑制体内的肿瘤发生。因此，半胱天冬酶 2 作为 NFκB 依赖性细胞存活的内源性抑制剂发挥作用，这种机制可能有助于人类的肿瘤抑制。
