The Stress-response protein prostate-associated gene 4, interacts with c-Jun and potentiates its transactivation.
The Stress-response protein prostate-associated gene 4, interacts with c-Jun and potentiates its transactivation.
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DOI：
10.1016/j.bbadis.2013.11.014
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发表时间：
2014-02
影响因子：
6.2
通讯作者：
Kulkarni, Prakash
中科院分区：
文献类型：
--
作者：
Rajagopalan, Krithika;Qiu, Ruoyi;Mooney, Steven M.;Rao, Shweta;Shiraishi, Takumi;Sacho, Elizabeth;Huang, Hongying;Shapiro, Ellen;Weninger, Keith R.;Kulkarni, Prakash
癌症/睾丸抗原（CTA），前列腺相关基因4（PAGE 4），是一种应激反应蛋白，在前列腺癌（PCa）中上调，特别是在炎症应激导致的前驱病变中。在应激下的细胞中，PAGE 4向线粒体的移位增加，而活性氧的产生减少。此外，PAGE 4在人胎儿前列腺中也上调，强调了其在发育中的潜在作用。然而，与PAGE 4相互作用的蛋白质及其在前列腺发育和疾病中的多效性功能的机制仍然未知。在这里，我们确定c-Jun作为PAGE 4相互作用的伙伴。我们发现，PAGE 4和c-Jun在人胎儿前列腺中过表达;在基于细胞的测定中，PAGE 4强烈增强c-Jun反式激活。单分子Förster共振能量转移实验表明，当与c-Jun结合时，PAGE 4经历构象变化。然而，在BSA或含有线粒体内膜二磷脂酰甘油脂质标志物心磷脂的单层囊泡存在下，未观察到相互作用。总之，我们的数据表明，PAGE 4特异性地与c-Jun相互作用，并且构象动力学可以解释其观察到的多效性功能。据我们所知，这是第一份证明CTA和原癌基因之间串扰的报告。使用小分子破坏PAGE 4/c-Jun相互作用可能代表PCa的新治疗策略。
The Cancer/Testis Antigen (CTA), Prostate-associated Gene 4 (PAGE4), is a stress-response protein that is upregulated in prostate cancer (PCa) especially in precursor lesions that result from inflammatory stress. In cells under stress, translocation of PAGE4 to mitochondria increases while production of reactive oxygen species decreases. Furthermore, PAGE4 is also upregulated in human fetal prostate, underscoring its potential role in development. However, the proteins that interact with PAGE4 and the mechanisms underlying its pleiotropic functions in prostatic development and disease remain unknown. Here, we identified c-Jun as a PAGE4 interacting partner. We show that both PAGE4 and c-Jun are overexpressed in the human fetal prostate; and in cell-based assays, PAGE4 robustly potentiates c-Jun transactivation. Single-molecule Förster resonance energy transfer experiments indicate that upon binding to c-Jun, PAGE4 undergoes conformational changes. However, no interaction is observed in presence of BSA or unilamellar vesicles containing the mitochondrial inner membrane diphosphatidylglycerol lipid marker cardiolipin. Together, our data indicate that PAGE4 specifically interacts with c-Jun and that, conformational dynamics may account for its observed pleiotropic functions. To our knowledge, this is the first report demonstrating crosstalk between a CTA and a proto-oncogene. Disrupting PAGE4/c-Jun interactions using small molecules may represent a novel therapeutic strategy for PCa.
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