A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization
A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization
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DOI：
10.1074/jbc.m602999200
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发表时间：
2006-06-23
影响因子：
4.8
通讯作者：
Gorodeski, George I.
中科院分区：
文献类型：
--
作者：
Feng, Ying-Hong;Li, Xin;Gorodeski, George I.
在宫颈癌细胞中发现了一种截短的自然发生的人类受体P2X(7)变体。新的蛋白(P2X(7-j))由258个氨基酸组成，缺乏全长P2X(7)受体的完整胞内羧基末端、第二跨膜结构域和胞外环的远端三分之一。P2X(7-j)在细胞膜上表达，其配体结合能力和通道功能减弱，不能形成孔洞，也不能介导细胞凋亡。P2X(7-j)与全长的P2X(7)以一种异位齐聚的方式相互作用，并阻断了P2X(7)介导的作用。有趣的是，在人癌组织和正常宫颈组织的裂解物中，P2X(7-j)的免疫反应和mRNA表达相似，但正常宫颈组织的全长P2X(7)免疫反应和mRNA表达高于癌组织，而癌组织中缺乏205 kDa的P2X(7)免疫反应，提示缺乏P2X(7)同源(Tri)齐聚。这些结果确定了一个新的具有凋亡抑制作用的P2X(7)变异体，并显示了一个截短的变异体通过异源寡聚拮抗其全长对应物的独特调节特性。这可能代表了通过其变体来调节蛋白质功能的一般范例。
A truncated naturally occurring variant of the human receptor P2X(7) was identified in cancer cervical cells. The novel protein (P2X(7-j)), a polypeptide of 258 amino acids, lacks the entire intracellular carboxyl terminus, the second transmembrane domain, and the distal third of the extracellular loop of the full-length P2X(7) receptor. The P2X(7-j) was expressed in the plasma membrane; it showed diminished ligand-binding and channel function capacities and failed to form pores and mediate apoptosis in response to treatment with the P2X(7) receptor agonist benzoyl-ATP. The P2X(7-j) interacted with the full-length P2X(7) in a manner suggesting hetero-oligomerization and blocked the P2X(7)-mediated actions. Interestingly, P2X(7-j) immunoreactivity and mRNA expression were similar in lysates of human cancer and normal cervical tissues, but full-length P2X(7) immunoreactivity and mRNA expression were higher in normal than in cancer tissues, and cancer tissues lacked 205-kDa P2X(7) immunoreactivity suggesting lack of P2X(7) homo(tri)-oligomerization. These results identify a novel P2X(7) variant with apoptosis-inhibitory actions, and demonstrate a distinct regulatory property for a truncated variant to antagonize its full-length counterpart through hetero-oligomerization. This may represent a general paradigm for regulation of a protein function by its variant.