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

负 MAPK-RAS-ERK 通路调节维持 CIC-DUX4 表达

• 批准号: 10818281
• 负责人: Ross Okimoto
• 金额: $ 7.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-17 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818281
• 关键词: Adolescent; Binding; Biochemical; Biological Assay; Cell Death; Cells; ChIP-seq; Child; Childhood; Chimeric Proteins; Clinical; DNA; DUSP6 protein; Data; Data Set; Ensure; Family member; Fusion Oncogene Proteins; Genetic; Genetic Transcription; Guanosine Triphosphate; Hyperactivity; Link; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Nuclear Export; Oncoproteins; Outcome; Pathway Analysis; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Plasmids; Process; Protein Family; Regulation; Role; Signal Transduction; Small Interfering RNA; Therapeutic; Transcriptional Regulation; Undifferentiated; candidate identification; effective therapy; experimental study; fusion gene; ineffective therapies; insight; knock-down; neoplastic cell; overexpression; parent grant; parent project; pharmacologic; protein degradation; response; sarcoma; small hairpin RNA; therapeutic target; transcription factor; transcriptomics; tumorigenesis; young adult; Adolescent; Binding; Biochemical; Biological Assay; Cell Death; Cells; ChIP-seq; Child; Childhood; Chimeric Proteins; Clinical; DNA; DUSP6 protein; Data; Data Set; Ensure; Family member; Fusion Oncogene Proteins; Genetic; Genetic Transcription; Guanosine Triphosphate; Hyperactivity; Link; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Nuclear Export; Oncoproteins; Outcome; Pathway Analysis; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Plasmids; Process; Protein Family; Regulation; Role; Signal Transduction; Small Interfering RNA; Therapeutic; Transcriptional Regulation; Undifferentiated; candidate identification; effective therapy; experimental study; fusion gene; ineffective therapies; insight; knock-down; neoplastic cell; overexpression; parent grant; parent project; pharmacologic; protein degradation; response; sarcoma; small hairpin RNA; therapeutic target; transcription factor; transcriptomics; tumorigenesis; young adult

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.

项目摘要/摘要 转录因子（TF）融合基因产生驱动肿瘤发生的癌蛋白。而TF融合 代表癌症特定的改变，直接治疗靶向仍然是临床挑战。一 示例是CIC-DUX4 TF融合，该融合定义了圆形细胞肉瘤的积极子集 儿童和年轻人。 CIC-DUX4患者的临床结果由于高而感到沮丧 转移倾向和无效疗法。目前，尚无疗法，即CIC- DUX4融合。为了满足这种需求，我们最近确定了终端之间的机械联系 MAPK信号基板，ERK和CIC-DUX4。具体而言，ERK物理结合和磷酸化 CIC-DUX4导致核输出快速出口，融合降解和肿瘤细胞死亡。自MAPK以来 信号传导是在正常和恶性过程中表达的普遍途径，我们想知道 CIC-DUX4融合如何保持自己的表达。通过生化和分子 研究我们已经确定了CIC-DUX4肉瘤细胞中负MAPK-ERK调节的关键作用。 因此，CIC-DUX4在转录上上调ERK特异性磷酸酶DUSP6，以限制ERK 活性，从而实现CIC-DUX4表达。最近，我们提出了一个意想不到的发现 CIC-DUX4表达也可以下调RAS活性。由于RAS是近端MAPK基板 我们假设CIC-DUX4限制了MAPK-RAS-ERK信号通量 在此规范信号级联的多个级别。该提议将定义CIC-DUX4如何 调节RAS活性，从而进一步维持CIC-DUX4表达。