The role of beclin 1/class III PI-3 kinase and p53 in breast tumorigenesis

描述(由申请人提供)：最近的基因敲除研究证实，Beclin 1是一种肿瘤抑制基因。然而，目前还不清楚Beclin 1是如何在肿瘤保护中发挥这样的作用的。我们的初步研究结果显示，在Beclin 1或hVps34缺陷的乳腺上皮细胞中，p53反应受到损害。有趣的是，有初步证据表明，hVps34与hdm2结合，hVps34缺陷细胞中hdm2的表达上调。由于Beclin 1和hVps34是III类PI-3激酶的主要成分，我们推测Beclin 1的抑瘤作用是通过Beclin 1/III PI-3激酶调节P53反应的能力来实现的。本研究的目的是全面研究P53/Hdm2与Beclin 1/III类PI-3激酶之间的关系。将采取多学科的方法来确定参与Beclin 1/III类PI-3激酶控制的途径和机制，并进而阐明它们如何在乳腺癌发生的背景下影响P53的反应。1)研究p53/Hdm2与Beclin 1/III类PI-3激酶之间的相互作用。2)阐明III类PI-3激酶介导的P53调控途径。3)研究Beclin 1/III类PI-3激酶在体内对P53的调节作用及其在乳腺肿瘤发生中的作用。通过这些研究，我们相信我们将能够对BECLIN1依赖的肿瘤抑制功能的机制提供见解。Beclin 1/III类PI-3激酶与Hdm2/P53之间的功能相互作用不仅代表了一种新的P53调控机制，而且也为观察到Hdm2在高达50%的乳腺癌中表达升高提供了新的线索，而在P53突变很少的乳腺癌中，Hdm2的表达上调，而在50%的乳腺癌中Hdm2的表达为单等位基因缺失。公共卫生相关性：这项拟议的研究将使我们能够对BECLIN1依赖的肿瘤抑制功能的机制提供见解。Beclin 1/III类PI-3激酶与Hdm2/P53之间的功能相互作用不仅代表了一种新的P53调控机制，而且也为观察到Hdm2在高达50%的乳腺癌中表达升高提供了新的线索，而在P53突变很少的乳腺癌中，Hdm2的表达上调，而在50%的乳腺癌中Hdm2的表达为单等位基因缺失。

DESCRIPTION (provided by applicant): Gene knockout studies have recently established beclin 1 as a tumor suppressor gene. However, it is unclear how beclin 1 plays such a role in protection of malignancies. Results from our preliminary studies revealed a compromised p53 response in beclin 1- or hVps34-deficient breast epithelial cells. Of interest are the preliminary evidences that hVps34 binds to hdm2 and the expression of hdm2 is elevated in hVps34 deficient cells. Since beclin 1 and hVps34 are the major components of class III PI-3 kinase, we hypothesize that the tumor suppressor function of beclin 1 is mediated by the ability of beclin 1/class III PI-3 kinase to regulate the p53 response. The aim of this study is to fully characterize the link between p53/hdm2 and beclin 1/class III PI-3 kinase. A multidisciplinary approach will be taken to identify pathways and mechanisms involved in beclin 1/class III PI-3 kinase control, and in turn clarify how they impact on the p53 response in the context of breast carcinogenesis. Three aims are proposed: 1) To characterize the interaction between p53/hdm2 and beclin 1/class III PI-3 kinase. 2) To elucidate pathways involved in the class III PI-3 kinase-mediated p53 control. 3) To examine the role of beclin 1/class III PI-3 kinase-mediated regulation of p53 in vivo and in breast tumorigenesis. Through these lines of investigation, we are confident that we will be able to offer insights into the mechanisms of beclin 1-dependent tumor suppressor function. The functional interaction between beclin 1/class III PI-3 kinase and hdm2/p53 would not only represent a novel mechanism of p53 regulation but also shed some light on the observations that the expression of hdm2 is elevated in as many as 50% of human breast cancer where few p53 mutation is found and, beclin 1 is monoallelic deleted in 50% of breast cancer. PUBLIC HEALTH RELEVANCE: The proposed study will enable us to able to offer insights into the mechanisms of beclin 1-dependent tumor suppressor function. The functional interaction between beclin 1/class III PI-3 kinase and hdm2/p53 would not only represent a novel mechanism of p53 regulation but also shed some light on the observations that the expression of hdm2 is elevated in as many as 50% of human breast cancer where few p53 mutation is found and, beclin 1 is monoallelic deleted in 50% of breast cancer.