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，这些分子在调节细胞增殖和细胞死亡之间的平衡方面起着至关重要的作用。其中一种受体CD30的解除调控与包括霍奇金氏病和间变性大细胞淋巴瘤在内的几种疾病有关。CD30被其同源配体激活或通过与激动型抗体交联可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仍不清楚。我们和其他人研究了CD30利用的信号转导途径。肿瘤坏死因子受体相关因子(TRAF)与CD30、CD40和2型肿瘤坏死因子受体的胞浆区元件结合，可激活多效性转录因子NF-kappaB和丝氨酸氨基末端激酶JNK(c-jun N-末端激酶)家族。核转录因子kappaB和JNK都参与了细胞存活的调节。我们还发现，CD30的激活导致TRAF2的蛋白降解，在间变性大细胞淋巴瘤细胞中，这被认为导致无法激活核因子kappaB，并对其他促凋亡刺激敏感。利用各种淋巴瘤和白血病细胞系，以及一系列CD30激动型抗体，我们正在研究CD30激活在细胞培养系统中以及在小鼠模型中的作用。我们的数据表明，CD30导向的靶向策略在治疗CD30阳性的恶性肿瘤方面可能具有巨大的潜力。

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.