Characterisation of the role of dual-specific MAP kinase phosphatases in androgen receptor action in prostate cancer development

丝裂原活化蛋白激酶（MAPK）途径通过磷酸化信号级联中的关键分子在肿瘤进展中发挥重要作用。其作用的一个主要决定因素是激酶活性的持续时间和大小，而激酶活性又受MAPK磷酸酶的调节。MAPK磷酸酶的一个实例是双特异性磷酸酶（DUSP）家族，其涉及许多癌症，特别是前列腺癌的发展。雄激素受体（AR）是一种配体激活的转录因子，在前列腺癌的发生发展中也起着重要作用。其作用受雄激素、雄激素拮抗剂和可逆磷酸化事件调节。该项目的目的是确定不同的哺乳动物DUSPs如何改变AR磷酸化并影响前列腺癌发展和前列腺癌治疗期间抗雄激素抵抗的AR作用。本研究的实验方法是通过siRNA技术敲低不同DUSPs的表达，并确定这对前列腺肿瘤发展不同阶段的AR磷酸化和基因调控网络的影响。本研究的另一个目的是从机制上确定DUSP表达的敲低如何有助于前列腺癌治疗中的抗雄激素抗性。这些研究将提供有价值的信息，DUSP靶向前列腺癌的未来治疗。

Mitogen-activated protein kinase (MAPK) pathways play an important role in tumour progression by phosphorylating key molecules in signalling cascades. A major determinant of their action is the dura-tion and magnitude of the kinase activity, which in turn is regulated by MAPK phosphatases. One example of MAPK phosphatases is the dual-specific phosphatase (DUSP) family, which is implicated in the development of many cancers, especially prostate cancer. Androgen receptor (AR), a ligandac-tivated transcription factor also plays an essential role in prostate cancer development. Its action is regulated by androgens, androgen antagonists and reversible phosphorylation events. The aim of the project is to determine how different mammalian DUSPs can alter AR phosphorylation and influence AR action in prostate cancer development and in anti-androgen resistance during prostate cancer therapy. The experimental approach to this study is to knock down the expression of the different DUSPs by siRNA technique and to determine the impact this would have on AR phosphorylation and gene regulatory networks at different stages of prostate tumour development. A further objective of this study is to determine mechanistically how knock-down of DUSP expression contributes to anti-androgen resistance in prostate cancer therapy. These studies will provide valuable information on which DUSP to target pharmacologically in the future treatment of prostate cancer.