Negative MAPK-RAS-ERK pathway regulation to sustain CIC-DUX4 expression

项目总结/摘要 转录因子（TF）融合基因产生驱动肿瘤发生的癌蛋白。虽然TF融合 尽管这些基因突变代表癌症特异性改变，但直接治疗靶向仍然是临床挑战。一 一个例子是CIC-DUX 4 TF融合，它定义了一个侵袭性的圆细胞肉瘤亚群， 儿童和年轻人。CIC-DUX 4患者的临床结果仍然令人沮丧，因为高 转移倾向和无效治疗。目前，还没有直接靶向CIC的治疗方法- DUX 4融合。为了满足这一需求，我们最近确定了一种机械连接， MAPK信号传导底物、ERK和CIC-DUX 4。具体来说，ERK物理结合并磷酸化 CIC-DUX 4导致快速核输出、融合降解和肿瘤细胞死亡。自从MAPK 信号传导是一种普遍存在的途径，在正常和恶性过程中表达，我们想知道， CIC-DUX 4融合体如何维持其自身的表达。通过生物化学和分子 我们的研究已经确定了负MAPK-ERK调节在CIC-DUX 4肉瘤细胞中的关键作用。 因此，CIC-DUX 4转录上调ERK特异性磷酸酶DUSP 6，以限制ERK 活性，从而能够表达CIC-DUX 4。最近，我们有了一个意想不到的发现， CIC-DUX 4表达也可下调RAS活性。由于RAS是近端MAPK底物， 由于CIC-DUX 4不被DUSP 6靶向，我们假设CIC-DUX 4限制了MAPK-RAS-ERK信号传导通量， 在这个典型的信号级联中的多个水平上。该提案将定义CIC-DUX 4如何 调节RAS活性，从而进一步维持CIC-DUX 4表达。

Project Summary/Abstract Transcription factor (TF) fusion genes create oncoproteins that drive tumorigenesis. While TF fusions represent cancer specific alterations, direct therapeutic targeting remains a clinical challenge. One example is the CIC-DUX4 TF fusion which defines an aggressive subset of round cell sarcoma in children and young adults. The clinical outcomes for CIC-DUX4 patients remain dismal due to high metastatic propensity and ineffective therapies. Currently, no therapies exist that direclty target the CIC- DUX4 fusion. To meet this need, we have recently identified a mechanistic link between the terminal MAPK signaling substrate, ERK, and CIC-DUX4. Specifically, ERK physically binds and phosphorylates CIC-DUX4 leading to rapid nuclear export, degradation of the fusion, and tumor cell death. Since MAPK signaling is a ubiquitous pathway expressed in both normal and malignant processes, we wondered how the CIC-DUX4 fusion could maintain its own expression. Through biochemical and molecular studies we have identified a key role for negative MAPK-ERK regulation in CIC-DUX4 sarcoma cells. Whereby, CIC-DUX4 transcriptionally upregulates the ERK specific phosphatase, DUSP6, to limit ERK activity and thus enable CIC-DUX4 expression. More recently, we made an unexpected finding that CIC-DUX4 expression could also downregulate RAS activity. Since RAS is a proximal MAPK substrate not targeted by DUSP6, we hypothesized that CIC-DUX4 was limiting MAPK-RAS-ERK signaling flux at multiple levels within this canonical signaling cascade. This proposal will define how CIC-DUX4 is regulating RAS activity, thus further sustaining CIC-DUX4 expression.