REGULATION OF THE PTEN GENE IN PROSTATE CANCER

PTEN肿瘤抑制基因在包括前列腺在内的许多人类癌症中起着关键作用。PTEN编码一种脂质磷酸酶，该酶在调节PI3-激酶/Akt信号通路中起关键作用，这为PTEN功能缺失导致癌症提供了令人信服的解释。我们的研究小组已经表明：(i)在高达50%的晚期前列腺癌患者中，PTEN功能丧失；（ii） PTEN调控前列腺癌细胞中pi3激酶/Akt通路；（iii） PTEN在前列腺细胞和脑细胞中结合多pdz支架蛋白（MAGI-2）； （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肿瘤抑制活性的影响，以及通过检测MAGI-2/PTEN复合物在通过pi3激酶/Akt通路维持信号完整性中的重要性，来详细表征MAGI-2对PTEN的调控。我们还将通过研究MAGI-2在前列腺癌和脑癌中的表达谱来研究其本身在肿瘤发生中发挥作用的可能性。最后，我们将通过创建PTEN c端MAGI-2结合域的靶向缺失和创建MAGI-2敲除小鼠来研究MAGI-2/PTEN相互作用在整个动物背景下的重要性。总之，这些实验将定义人类癌症中PTEN调控的新模式。

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.