REGULATION OF THE PTEN TUMOR SUPPRESSOR GENE IN PROSTATE CANCER

描述(申请人提供)：PTEN肿瘤抑制基因发挥作用 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中起关键作用的脂磷酸酶 信号通路，为PTEN的缺失提供了令人信服的解释 功能失调会导致癌症。我们的研究小组已经证明：(I)PTEN功能丧失 在高达50%的晚期前列腺癌中；(Ii)PTEN调节PI3- 前列腺癌细胞中的KK/Akt通路；(Iii)PTEN结合多个PDZ 前列腺和脑细胞中的支架蛋白(MAGI-2)和(Iv)MAGI-2可以 调节PTEN的磷酸酶活性。在这里，我们建议将 MAGI-2对PTEN的调控作用 PTEN的抑癌活性以及通过检测PTEN在肿瘤抑制中的作用 MAGI-2/PTEN复合体在维持PI3-信号完整性中的作用 激酶/Akt通路。我们还将研究MAGI-2本身 通过对其表达谱的研究，可能在肿瘤的发生中发挥作用 前列腺癌和脑癌。最后，我们将研究 MAGI-2/PTEN在整个动物环境中的相互作用 PTEN C末端MAGI-2结合域的缺失 创造了MAGI-2基因敲除鼠标。总之，这些实验将定义一个 人类肿瘤中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.