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

描述（由申请人提供）：基因敲除研究最近确定beclin 1是一种肿瘤抑制基因。然而，目前尚不清楚beclin 1如何在恶性肿瘤的保护中发挥这样的作用。我们的初步研究结果显示，在beclin 1-或hvs34缺陷的乳腺上皮细胞中，p53反应受损。令人感兴趣的是hVps34与hdm2结合的初步证据，hdm2的表达在hVps34缺陷细胞中升高。由于beclin 1和hVps34是III类PI-3激酶的主要成分，我们假设beclin 1的肿瘤抑制功能是由beclin 1/ III类PI-3激酶调节p53反应的能力介导的。本研究的目的是充分表征p53/hdm2与beclin 1/ III类PI-3激酶之间的联系。将采用多学科方法来确定beclin 1/ III类PI-3激酶控制的途径和机制，并反过来阐明它们如何影响乳腺癌发生背景下的p53反应。我们提出了三个目标：1)表征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调控通路。3)探讨beclin 1/ III类PI-3激酶介导的p53在体内和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深入了解beclin - 1依赖性肿瘤抑制功能的机制。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p53调控的新机制，而且还揭示了hdm2在多达50%的人类乳腺癌中表达升高而p53突变很少，beclin 1在50%的乳腺癌中是单等位基因缺失的观察结果。公共卫生相关性：拟议的研究将使我们能够深入了解beclin 1依赖性肿瘤抑制功能的机制。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p53调控的新机制，而且还揭示了hdm2在多达50%的人类乳腺癌中表达升高而p53突变很少，beclin 1在50%的乳腺癌中是单等位基因缺失的观察结果。

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.