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

双特异性MAP激酶（MAPK）磷酸酶（DUSPs或MKPs）是MAPK通路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通路在多种人类癌症中异常激活，包括肺癌、胰腺癌和恶性黑色素瘤。此外，随着癌症的发展，MKP的表达通常会减少或增加，这表明MKP通过调节途径活性可能会影响肿瘤的发生和/或发展。生长因子诱导磷酸酶DUSP 6/MKP-3是细胞质中经典ERK 1和ERK 2 MAPK的特异性负反馈调节剂。我们已经产生了携带条件（floxed）DUSP 6等位基因的小鼠，并正在研究基因丢失在培养细胞和小鼠癌症模型中的影响。到目前为止，我们已经证明DUSP 6/MKP-3的缺失使小鼠对DMBA/TPA诱导的皮肤癌发生敏感，证明了这种磷酸酶的肿瘤抑制作用。目前和未来的研究旨在确定DUSP 6/MKP-3是否在临床相关组织（如胰腺和肺）中突变Ras诱导的肿瘤中发挥更广泛的作用，并使用从这些动物培养的组织和细胞系来确定受DUSP 6缺失影响的相关MAPK靶点，以及这些靶点如何促进癌症发展。

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.