The role of dual-specificity phosphatase 6 (DUSP6) in modulating the oncogenic potential of Ras/ERK signalling

双特异性磷酸酶 6 (DUSP6) 在调节 Ras/ERK 信号传导致癌潜力中的作用

• 批准号: 287328325
• 负责人: Dr. Julia Stellzig
• 金额: --
• 依托单位: CR-UK Stress Response Laboratory
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/287328325?language=en
• 关键词: role; dual; specificity; phosphatase; DUSP6

Dual-specificity MAP kinase (MAPK) phosphatases (DUSPs or MKPs) are key negative regulators of MAPK pathway activity and thus the biological outcome of signalling. The Ras-Raf-ERK pathway is abnormally activated in a wide variety of human cancers, including lung, pancreas and malignant melanoma. Furthermore, the expression of MKPs is often either reduced or increased as cancers develop indicating that MKPs, by modulating pathway activity, may influence tumour initiation and/or development. The growth factor inducible phosphatase DUSP6/MKP-3 is a specific negative feedback regulator of the classical ERK1 and ERK2 MAPKs in the cytoplasm. We have generated mice carrying a conditional (floxed) DUSP6 allele and are studying the effects of gene loss in both cultured cells and in mouse models of cancer. Thus far, we have demonstrated that deletion of DUSP6/MKP-3 sensitises mice to DMBA/TPA-inducible skin carcinogenesis, demonstrating a tumour suppressor role for this phosphatase. Current and future studies are aimed at determining if DUSP6/MKP-3 plays a wider role in mutant Ras-induced tumours in more clinically relevant tissues such as pancreas and lung and to use both tissues and cell lines cultured from these animals to determine the relevant MAPK targets affected by DUSP6 deletion and how these might act to promote cancer development.

双特异性MAP激酶（MAPK）磷酸酶（DUSPS或MKP）是MAPK途径活性的关键负调节剂，因此是信号传导的生物学结果。 RAS-RAF-ERK途径在包括肺，胰腺和恶性黑色素瘤在内的各种人类癌症中被异常激活。此外，随着癌症的发展，MKP的表达通常会降低或增加，这表明MKP通过调节途径活动可能会影响肿瘤起始和/或发育。生长因子诱导的磷酸酶DUSP6/MKP-3是细胞质中经典ERK1和ERK2 MAPK的特定负反馈调节剂。我们已经产生了携带条件（Floxed）DUSP6等位基因的小鼠，并正在研究培养细胞和小鼠癌症模型中基因丧失的影响。到目前为止，我们已经证明DUSP6/MKP-3的缺失使小鼠对DMBA/TPA诱导的皮肤致癌作用，这表明该磷酸酶的肿瘤抑制作用作用。当前和将来的研究旨在确定DUSP6/MKP-3在突变体RAS诱导的肿瘤中是否起着更广泛的作用，例如胰腺和肺部等临床相关的组织，并使用这些动物培养的组织和细胞系来确定由DUSP6 DETETION和如何促进这些促进癌症发展的相关MAPK靶标。