Oligomerization domain of the multidrug resistance-associated transporter ABCG2 and its dominant inhibitory activity
Oligomerization domain of the multidrug resistance-associated transporter ABCG2 and its dominant inhibitory activity
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DOI：
10.1158/0008-5472.can-06-3169
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Zhang, Jian-Ting
中科院分区：
文献类型：
--
作者：
Xu, Junkang;Peng, Hui;Zhang, Jian-Ting
癌细胞中人 ATP 结合盒转运蛋白 ABCG2 的过度表达通过流出抗癌药物而导致多药耐药性。 ABCG2 被认为是半转运蛋白，并被认为以同二聚体的形式发挥作用。然而，最近的证据表明它可能以由 12 个亚基组成的高级形式的寡聚物存在。在本研究中，我们将人ABCG2的寡聚结构域映射到其由TM5-环-TM6组成的跨膜结构域。当在 HEK293 细胞中单独表达时，该寡聚化结构域也形成同源十二聚体。此外，该结构域具有抑制药物流出和全长 ABCG2 的耐药功能的活性，可能是通过破坏同源寡聚全长 ABCG2 的形成。这些发现表明，人类 ABCG2 可能存在并通过位于 TM5-loop-TM6 中的相互作用作为同源寡聚体发挥作用，并且 ABCG2 寡聚化可用作治疗开发的靶标，以规避癌症治疗中 ABCG2 介导的耐药性。
overexpression of human ATP-binding cassette transporter ABCG2 in cancer cells causes multidrug resistance by effluxing anticancer drugs. ABCG2 is considered as a half transporter and is thought to function as a homodimer. However, recent evidence suggests that it may exist as a higher form of oligomer consisting of 12 subunits. In this study, we mapped the oligomerization domain of human ABCG2 to its transmembrane domain consisting of TM5-loop-TM6. This oligomerization domain, when expressed alone in HEK293 cells, also forms a homododecamer. Furthermore, this domain has activity that inhibits drug efflux and resistance function of the full-length ABCG2 likely by disrupting the formation of the homo-oligomeric full-length ABCG2. These findings suggest that human ABCG2 may exist and work as a homo-oligomer by interactions located in TM5-loop-TM6, and that ABCG2 oligomerization may be used as a target for therapeutic development to circumvent ABCG2-mediated drug resistance in cancer treatment.