2012年8月16日 讯 /生物谷BIOON/ --一项新的研究发现了黑色素瘤治疗的潜在新靶标,黑色素瘤是一种最致命的皮肤癌。Silvia Penuela和Dale Laird发现了一个新的通道形成蛋白Pannexin(Panx1)在健康的皮肤细胞表面上处于正常水平。但他们发现,黑色素瘤中,Panx1是过度生成的,是处于一种病态水平的。研究人员还发现,如果减少或敲除其表达,能使瘤细胞变得正常。这项研究发表在8月17日的Journal of Biological Chemistry杂志上。
恶性黑色素瘤占所有皮肤癌的4%,然而,79%皮肤癌患者死于黑色素瘤。世界卫生组织说,每年有200万人诊断患有黑色素瘤和65万黑色素瘤患者死亡(2000年统计数字)。
我们认为Panx1多度生成使黑色素瘤细胞成为更具侵略性,有了这些额外Panx1蛋白,黑色素瘤细胞可以离开原发肿瘤和入侵其它组织。
当你找到在疾病如黑色素瘤细胞中一个高度上调的蛋白质,问题就变成如何寻找有治疗价值的靶向该蛋白质的药物,以减少其生成或阻止其功能。
我们现在希望通过与伦敦健康科学中心的Muriel Brackstone博士等其他医生的合作,使用人黑色素瘤患者样本确定其是否是一个肿瘤标志物。假如黑色素瘤病变确实伴随大量的这种蛋白高表达,那么该蛋白可能是预后指标。 (生物谷:Bioon.com)
编译自:Potential new treatment target identified for melanoma skin cancer
doi:10.1074/jbc.M109.004804
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The Pannexin 1 Channel Activates the Inflammasome in Neurons and Astrocytes*
William R. Silverman, Juan Pablo de Rivero Vaccari§, Silviu Locovei, Feng Qiu, et al.
The inflammasome is a multiprotein complex involved in innate immunity. Activation of the inflammasome causes the processing and release of the cytokines interleukins 1β and 18. In primary macrophages, potassium ion flux and the membrane channel pannexin 1 have been suggested to play roles in inflammasome activation. However, the molecular mechanism(s) governing inflammasome signaling remains poorly defined, and it is undetermined whether these mechanisms apply to the central nervous system. Here we show that high extracellular potassium opens pannexin channels leading to caspase-1 activation in primary neurons and astrocytes. The effect of K+ on pannexin 1 channels was independent of membrane potential, suggesting that stimulation of inflammasome signaling was mediated by an allosteric effect. The activation of the inflammasome by K+ was inhibited by the pannexin 1 channel blocker probenecid, supporting a role of pannexin 1 in inflammasome activation. Co-immunoprecipitation of neuronal lysates indicates that pannexin 1 associates with components of the multiprotein inflammasome complex, including the P2X7 receptor and caspase-1. Moreover antibody neutralization of the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) blocked ATP-induced cell death in oocytes co-expressing P2X7 receptor and pannexin 1. Thus, in contrast to macrophages and monocytes in which low intracellular K+ has been suggested to trigger inflammasome activation, in neural cells, high extracellular K+ activates caspase-1 probably through pannexin 1.