Role of BAG1 in suppressing the intrinsic tumor suppressor activity of MYC

描述（由申请方提供）：异常MYC表达是人类癌症中常见的致癌事件。有趣的是，MYC可以驱动细胞周期进程或诱导细胞凋亡。MYC诱导细胞凋亡的潜在能力被称为“内在肿瘤抑制活性”，并且在肿瘤中重新激活这种细胞凋亡功能被广泛认为是有价值的治疗目标。作为一种转录因子，MYC控制着许多下游靶点的表达，对于其中的大多数靶点，它们是否在MYC功能中发挥直接作用仍不清楚。为了鉴定生物活性所需的特定基因子集，我们对功能重要的MYC靶标进行了筛选，并鉴定了BAG1，其编码促生存分子伴侣蛋白。在乳腺癌小鼠模型和转化的人细胞中，BAG1的表达受MYC的调节。值得注意的是，BAG1诱导对于保护细胞免受MYC诱导的凋亡是绝对必要的。最终，我们已经确定了MYC过表达和BAG1抑制之间的合成致死性，建立了一个新的途径，可以利用它来重新激活MYC作为癌症治疗的潜在凋亡潜力。本文提出的研究将定义这一新途径的参数，并建立其作为治疗靶点的临床前证据。

DESCRIPTION (provided by applicant): Aberrant MYC expression is a common oncogenic event in human cancer. Paradoxically, MYC can either drive cell cycle progression or induce apoptosis. The latent ability of MYC to induce apoptosis has been termed "intrinsic tumor suppressor activity", and reactivating this apoptotic function in tumors is widely considered a valuable therapeutic goal. As a transcription factor, MYC controls the expression of many downstream targets and for the majority of these it remains unclear whether or not they play direct roles in MYC function. To identify the subset of genes specifically required for biological activity, we conducted a screen for functionally important MYC targets, and identified BAG1, which encodes a pro-survival chaperone protein. Expression of BAG1 is regulated by MYC in both a mouse model of breast cancer and in transformed human cells. Remarkably, BAG1 induction is absolutely required for protecting cells from MYC-induced apoptosis. Ultimately, the synthetic lethality we have identified between MYC overexpression and BAG1 inhibition, establishes a new pathway that might be exploited to reactivate the latent apoptotic potential of MYC as a cancer therapy. The studies proposed here will define the parameters of this new pathway and establish pre- clinical evidence of its utility as a therapeutic target.