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

描述(申请人提供)：异常的MYC表达是人类癌症中常见的致癌事件。矛盾的是，MYC既可以推动细胞周期进程，也可以诱导细胞凋亡。MYC潜在的诱导细胞凋亡的能力被称为“固有的肿瘤抑制活性”，在肿瘤中重新激活这一凋亡功能被广泛认为是一个有价值的治疗目标。作为一种转录因子，MYC控制着许多下游靶点的表达，对于大多数下游靶点来说，它们是否在MYC功能中发挥直接作用尚不清楚。为了确定生物活性所需的特定基因子集，我们对重要的MYC靶标进行了筛选，并鉴定了BAG1，它编码一种有利于生存的伴侣蛋白。在乳腺癌的小鼠模型和转化的人类细胞中，BAG1的表达都受到MYC的调节。值得注意的是，BAG1的诱导是保护细胞免受MYC诱导的细胞凋亡所必需的。最终，我们已经确定的MYC过表达和BAG1抑制之间的合成致命性，建立了一条新的途径，可能被利用来重新激活MYC的潜在凋亡潜力作为癌症治疗。这里提出的研究将确定这一新途径的参数，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.