TM4SF3 and AR: A Nuclear Complex that Stabilizes Both Proteins
TM4SF3 and AR: A Nuclear Complex that Stabilizes Both Proteins
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DOI：
10.1210/me.2015-1075
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发表时间：
2016-01-01
影响因子：
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通讯作者：
Shemshedini, Lirim
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文献类型：
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作者：
Bhansali, Meenakshi;Zhou, Jun;Shemshedini, Lirim
跨膜蛋白4超家族3（Transmembrane 4 superfamily 3，TM 4SF 3）是前列腺癌（prostate cancer，PCa）细胞中一个新的雄激素调节基因。我们的数据表明，TM 4SF 3表现出雄激素诱导的mRNA的抑制，但上调的蛋白质。考虑到雄激素和四跨膜蛋白两者的促癌功能，雄激素对TM 4SF 3蛋白的积极作用具有重要意义。雄激素通过抑制TM 4SF 3蛋白的蛋白酶体依赖性降解来正向调节其稳定性。TM 4SF 3的这种雄激素稳定性参与促进雄激素依赖性和雄激素非依赖性PCa细胞的PCa细胞侵袭和迁移。虽然证实雄激素上调TM 4SF 3蛋白，我们观察到，TM 4SF 3不仅定位于膜，而且，令人惊讶的是，PCa细胞的细胞核。这种新的核定位TM 4SF 3依赖于雄激素诱导的雄激素受体（AR）的核定位在雄激素依赖性和雄激素非依赖性前列腺癌细胞系。TM 4SF 3在PCa细胞类型和体外与AR相互作用，强烈表明直接相互作用。这种直接的相互作用不仅是TM 4SF 3稳定所必需的，而且也是显著的AR稳定所必需的，因为TM 4SF 3的下调导致AR蛋白水平的降低。作为一种重要的AR调节因子，TM 4SF 3调节前列腺癌细胞中雄激素依赖性基因的表达和增殖。重要的是，在前列腺肿瘤中也观察到AR和TM 4SF 3蛋白水平与核共定位之间的直接相关性，这强烈表明在肿瘤中发现了由AR-TM 4SF 3相互作用引起的相互稳定，并且这种相互作用在PCa生物学中是重要的。
Transmembrane 4 superfamily 3 (TM4SF3) was identified as a novel androgen-regulated gene in prostate cancer (PCa) cells. Our data demonstrate that TM4SF3 exhibits androgen-induced repression of the mRNA but up-regulation of the protein. The androgen positive effect on the TM4SF3 protein is of significant interest in view of the procancer functions of both androgens and tetraspanin proteins. Androgen positively regulates TM4SF3 protein stability by inhibiting its proteasome-dependent degradation. This androgen stabilization of TM4SF3 is involved in promoting PCa cell invasion and migration of both androgen-dependent and androgen-independent PCa cells. Although confirming androgen up-regulation of the TM4SF3 protein, we observed that TM4SF3 is localized not only to the membrane, but also, surprisingly, the nuclei of PCa cells. This novel nuclear localization of TM4SF3 depends on androgen-induced nuclear localization of androgen receptor (AR) in both androgen-dependent and androgen-independent PCa cell lines. TM4SF3 interacts with AR both in PCa cell types and in vitro, strongly suggesting a direct interaction. This direct interaction is required for the stabilization of not only TM4SF3, but also remarkably AR, because down-regulation of TM4SF3 resulted in reduced AR protein levels. As expected of an important AR regulator, TM4SF3 regulates androgen-dependent gene expression in and proliferation of PCa cells. Importantly, a direct correlation between AR and TM4SF3 protein levels and nuclear colocalization were also observed in prostate tumors, strongly suggesting that the mutual stabilization resulting from the AR-TM4SF3 interaction is found in tumors and that this interaction is important in PCa biology.