Induction of Apoptosis in Lymphoma Cells by Activation of CD30

研究：肿瘤坏死因子受体超家族由许多相关的细胞表面分子组成，在调节细胞增殖和细胞死亡之间的平衡中起着至关重要的作用。其中一种受体CD30的失调与几种疾病有关，包括霍奇金病和间变性大细胞淋巴瘤。CD30通过其同源配体或通过与激动抗体交联激活可以诱导增殖或凋亡细胞死亡，这取决于细胞环境，尽管这种差异的分子基础尚不清楚。我们和其他人已经研究了CD30利用的信号转导途径。TNF受体相关因子（TRAFs）与CD30、CD40和2型TNF受体细胞质结构域的元件结合，已被证明可以激活多效转录因子NF κ B，以及丝氨酸-苏氨酸激酶家族的JNK （c-Jun n -末端激酶）。NF κ B和JNK都参与细胞存活的调控。我们还发现，CD30的激活会导致TRAF2的蛋白水解降解，在间变性大细胞淋巴瘤细胞中，这被认为会导致NF κ B的激活失败和对其他促凋亡刺激的致敏。使用多种淋巴瘤和白血病细胞系，以及一系列CD30激动抗体，我们正在研究CD30激活在细胞培养系统和小鼠模型中的作用。我们的数据表明，cd30定向靶向策略在治疗cd30阳性恶性肿瘤方面可能具有很大的潜力。

Research: The tumor necrosis factor receptor superfamily is comprised of a number of related cell surface molecules which play crucial roles in regulating the balance between cell proliferation and cell death. Deregulation of one of these receptors, CD30, has been implicated in several disorders including Hodgkin's disease and anaplastic large cell lymphoma. Activation of CD30 by its cognate ligand or by crosslinking with agonistic antibodies can induce either proliferation or apoptotic cell death, depending upon the cellular context, although the molecular basis of this disparity is still unclear. We and others have examined the signal transduction pathways utilized by CD30. The TNF receptor-associated factors (TRAFs), which bind to elements in the cytoplasmic domains of CD30, CD40, and the type 2 TNF receptor, have been shown to activate the pleiotropic transcription factor NF kappa B, as well as the JNK (c-Jun N-terminal kinase) family of serine-threonine kinases. Both NF kappa B and JNK have been implicated in the regulation of cell survival. We have also found that activation of CD30 leads to the proteolytic degradation of TRAF2, and in anaplastic large cell lymphoma cells this is thought to lead to the failure to activate NF kappa B and the sensitization to other pro-apoptotic stimuli. Using a variety of lymphoma and leukemia cell lines, as well as a range of CD30 agonistic antibodies, were are examining the effects of CD30 activation in cell culture systems as well as in murine models. Our data suggest that CD30-directed targeting strategies may have great potential in the treatment of CD30-positive malignancies.