Deciphering the role of the translational oncogenic program in Prostate Cancer

项目摘要： 我们一直处于建立癌症生物学新范式的前沿，通过证明 关键癌基因的关键功能，如Myc和mTOR，在增加核糖体生物合成和蛋白质 合成速率对于肿瘤发生至关重要。在上一个融资周期中，我们采用了多方面的 方法显示mTOR的特定下游翻译臂，4 EB 1-eIF 4 E，负责 重组前列腺癌（PCa）蛋白质组，并选择性地控制mRNA的翻译， 对癌细胞生长、代谢和转移至关重要。引人注目的是，我们还发现了一种新的RNA 这些mRNA的5 'UTR中的元件，我们称之为富含嘧啶的翻译元件（PRTE） 它划分了mTOR信号转导对翻译的选择性作用，并且在功能上是重要的。 控制此外，我们还发现，最具侵略性的形式的PCa，建立的损失， PTEN和MYC过度激活，诱导了深刻的“超级增强”蛋白质合成，必须小心处理。 通过激活适当的检查点来控制，以促进癌细胞存活。令人惊讶的是，我们发现， eIF 2 α的激活是一种特殊的手段来重新平衡蛋白质稳态作为适应性反应，以维持 PCa细胞存活。我们的遗传学和药理学的初步数据表明，eIF 2 α的磷酸化， 重编程翻译控制，代表了原发性和转移性PCa细胞的新的脆弱点。 这些研究结果共同为这一提议奠定了基础。在目标1中，我们将定义分子 反式作用蛋白识别并特异性结合PRTE以介导翻译的机制 PCa中mTOR下游的特异性。在目标2中，我们将阐明阻断P-eIF 2 α的确切益处。 活性和其他UPR武器在小鼠和人类PCa，这将铺平道路，新的治疗方法 以及确定新的治疗靶点来控制这种目前无法治愈的癌症。在目标3中， 还首次描述了由eIF 2 α指导的亚细胞定位翻译景观 前列腺蛋白质组在前列腺癌细胞中具有重要的磷酸化作用，以重编程维持细胞适应性所必需的前列腺蛋白质组。 总的来说，这些研究将提供一个新的理解转录后电路和合成的致命 这些网络可以重塑PCa蛋白质组，并可以作为新的疗法加以利用。

Project Abstract : We have been at the forefront of establishing a new paradigm in cancer biology, by demonstrating that a critical function of key oncogenes, such as Myc and mTOR, in augmenting ribosome biogenesis and protein synthesis rates is essential for tumorigenesis. In the previous funding cycle, we employed a multifaceted approach to show that a specific downstream translation arm of mTOR, 4EB1-eIF4E, is responsible for rewiring the prostate cancer (PCa) proteome and selectively controlling the translation of mRNAs that are critical for cancer cell growth, metabolism, and metastasis. Strikingly, we have also identified a new RNA element in the 5'UTR of these mRNAs, which we have termed the pyrimidine-rich translation element (PRTE) that demarcates and is functionally important for the selective actions of mTOR signaling on translational control. Furthermore, we have also discovered that the most aggressive form of PCa, established by loss of PTEN and MYC hyperactivation, induces profound “super-augmented” protein synthesis that must be carefully controlled by the activation of appropriate checkpoints to promote cancer cell survival. Strikingly, we find that activation of eIF2α is a specific means to rebalance protein homeostasis as an adaptive response to sustain PCa cell survival. Our genetic and pharmacological preliminary data show that phosphorylation of eIF2α, which reprograms translational control, represents a new point of vulnerability for primary and metastatic PCa cells. Together, these findings lay the foundation for this proposal. In Aim 1 we will define the molecular mechanisms by which trans-acting proteins recognize and specifically bind the PRTE to mediate translational specificity downstream of mTOR in PCa. In Aim 2 we will unravel the precise benefit of blocking P-eIF2α activity and other UPR arms in mice and human PCa, which will pave the way for new therapeutic approaches and the identification of novel therapeutic targets to reign in this currently incurable cancer. In Aim 3 we will also characterize for the first time the subcellular localized translational landscape directed by eIF2α phosphorylation to reprogram the prostate proteome essential in maintaining cellular fitness in PCa cells. Collectively, these studies will offer a new understanding of the post-transcriptional circuitry and synthetic lethal networks that remodel that PCa proteome and can be exploited as new therapies.