REGULATION OF THE PTEN GENE IN PROSTATE CANCER

PTEN抑癌基因在包括前列腺癌在内的许多人类癌症中起着关键作用。PTEN编码一种在调节PI3-激酶/Akt信号通路中起关键作用的脂质磷酸酶，为PTEN功能丧失导致癌症提供了令人信服的解释。我们的研究小组发现：(I)PTEN功能在高达50%的晚期前列腺癌中缺失；(Ii)PTEN调控前列腺癌细胞中的PI3-Kinase/Akt通路；(Iii)PTEN与前列腺和脑细胞中的多PDZ支架蛋白(MAGI-2)结合；以及(Iv)MAGI-2可以调节PTEN的磷酸酶活性。在这里，我们建议通过检测MAGI-2对PTEN抑瘤活性的影响以及MAGI-2/PTEN复合体在维持PI3-K/Akt通路信号完整性中的重要性来详细描述MAGI-2对PTEN的调节。我们还将通过研究MAGI-2在前列腺癌和脑癌中的表达情况，来研究MAGI-2本身可能在肿瘤发生中发挥作用的可能性。最后，我们将通过在PTEN的C末端创建有针对性的MAGI-2结合结构域的缺失和通过创建MAGI-2基因敲除小鼠来研究MAGI-2/PTEN相互作用在整个动物中的重要性。总之，这些实验将在人类癌症中定义一种新的PTEN调控模式。

The PTEN tumor suppressor gene plays a critical role in a number of human cancers, including prostate. PTEN encodes a lipid phosphatase that plays a key role in regulating the PI3- kinase/Akt signaling pathway, providing a compelling explanation of why loss of PTEN function leads to cancer. Our group has shown that: (i) PTEN unction is lost in up to 50 percent of advanced prostate cancers; (ii) PTEN regulates the PI3-kinase/Akt pathway in prostate cancer cells; (iii) PTEN binds a multi-PDZ scaffold protein (MAGI-2) in prostate and brain cells and (iv) MAGI-2 can regulate the phosphatase activity of PTEN. Here we propose to characterize the regulation of PTEN by MAGI-2 in detail by examining the effect of MAGI-2 on the tumor suppressor activity of PTEN and by examining the importance of the MAGI-2/PTEN complex in maintaining the integrity of signaling through the PI3-kinase/Akt pathway. We will also examine the possibility that MAGI-2 itself may play a role in oncogenesis through studies of its expression profile in prostate and brain cancers. Finally, we will study the importance of the MAGI-2/PTEN interaction in the context of a whole animal by creating targeted deletions of the MAGI-2 binding domain in the C-terminus of PTEN and by creating a MAGI-2 knockout mouse. Together, these experiments will define a novel mode of PTEN regulation in human cancers.