REGULATION OF THE PTEN TUMOR SUPPRESSOR GENE IN PROSTATE CANCER

描述（由申请人提供）：PTEN肿瘤抑制基因起着重要的作用。 在包括前列腺在内的许多人类癌症中起关键作用。PTEN编码 一种在调节PI3-激酶/Akt中起关键作用的脂质磷酸酶 信号通路，提供了一个令人信服的解释，为什么损失的PTEN 功能导致癌症。我们的小组已经表明：（i）PTEN功能丧失 在高达50%的晚期前列腺癌中;（ii）PTEN调节PI3- （iii）PTEN结合多-PDZ 支架蛋白（MAGI-2）在前列腺和脑细胞中的作用，以及（iv）MAGI-2可以 调节PTEN的磷酸酶活性。在这里，我们建议将 通过检查MAGI-2对PTEN的作用，详细地研究了MAGI-2对PTEN的调节。 PTEN的肿瘤抑制活性，并通过检查 MAGI-2/PTEN复合物在维持通过PI3 - 1信号传导的完整性中的作用 激酶/Akt途径。我们还将研究MAGI-2本身 可能在肿瘤发生中起作用，通过研究其在 前列腺癌和脑癌。最后，我们将研究 在整个动物的背景下，通过产生靶向的MAGI-2/PTEN相互作用， 在PTEN的C-末端中的MAGI-2结合结构域的缺失，以及 制造MAGI-2基因敲除小鼠。总之，这些实验将定义一个 人类癌症中PTEN调控的新模式。

DESCRIPTION (provided by applicant): 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 function 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.