PTEN Nuclear-Cytoplasmic Localization in Breast Cancer

描述(申请人提供)：肿瘤抑制基因，如PTEN，已被证明在散发性乳腺癌的发生中起着重要的躯体作用。PTEN的脂磷酸酶活性作为细胞质Pisk/Akt途径的负调节因子的作用是众所周知的。免疫组织化学研究首次证明PTEN存在于细胞核内。然而，对非细胞质PTEN在调节细胞通路中的作用知之甚少。越来越多的遗传学、病理学和生化证据有力地表明，PTEN的核浆分裂在肿瘤的发生中起着重要作用。到目前为止，关于PTEN核导入的机制及其对核信号通路的影响，特别是在癌变过程中核质信号之间的相互作用，人们还知之甚少。我们已经在PTEN中发现了非传统的核定位信号(NLS)，并表明这些NLS在与主要跳跃蛋白(MVP)的相互作用中起着关键作用。MVP是一种潜在的细胞质-核穿梭蛋白。我们和其他人之前已经报道了Akt在包括乳腺癌在内的许多浸润性癌症的细胞核中的激活增强。此外，侵袭性与核PTEN表达的缺失有关，这表明PTEN/Akt信号的调节和在核中的定位可能在肿瘤进展中起重要作用。我们已经鉴定并鉴定了Akt的核输出结构域，并证明了Akt的核激活足以在体外诱导细胞迁移。我们的数据表明，PTEN能够调节Akt亚细胞在细胞核中的定位和激活，从而定义了一种在肿瘤进展中核PTEN丢失的机制。因此，我们假设，核PTEN是细胞周期停滞所必需的，其核质分裂的改变是PTEN对核质Akt的调节机制之一。为了解决我们的假设，我们建议：1：研究核PTEN在细胞功能和维持细胞周期停滞中的作用；2：确定核PTEN定位的机制；3：评估核PTEN作为核Akt活性和定位的负调控因子的作用。当这些研究完成后，我们将对核PTEN作为肿瘤抑制因子在乳腺癌发生中的作用有更多的基础知识。这些数据还可能有助于乳腺癌的药物开发，并为治疗和预防提供新的靶点。

DESCRIPTION (provided by applicant): Tumor suppressor genes, such as PTEN, have been shown to play an important somatic role in sporadic breast carcinogenesis. The role of PTEN's lipid phosphatase activity as a negative regulator of the cytoplasmic PISK/Akt pathway is well known. Immunohistochemical studies were the first to suggest that PTEN exists in the nucleus. However, little is known about the role of non-cytoplasmic PTEN in regulating cellular pathways. Accumulating genetic, pathologic and biochemical evidence strongly suggests that nuclear-cytoplasmic partitioning of PTEN plays a role in carcinogenesis. To date, little is known about the mechanism of PTEN nuclear import or its impact on nuclear signaling pathways, particularly the cross talk between the nuclear and cytoplasmic signaling during carcinogenesis. We have identified non-traditional nuclear localization signals (NLS) in PTEN and showed that these NLS are critical for interaction with Major Vault Protein (MVP), a potential cytoplasmic-nuclear shuttling protein. We and others have previously reported enhanced activation of Akt in the nucleus of many invasive cancers, including breast malignancies. Additionally, the invasion has been associated with loss of nuclear PTEN expression, indicating that regulation of PTEN/Akt signaling and localization in the nucleus may be important in tumor progression. We have identified and characterized a functional nuclear export domain of Akt and demonstrated that nuclear Akt activation is sufficient to induce cell migration in vitro. Our data suggest that PTEN is capable of regulating Akt sub-cellular localization and activation in the nucleus, thereby defining a mechanism for nuclear PTEN loss in tumor progression. Thus, we hypothesize that nuclear PTEN is required for cell cycle arrest and alterations in the nuclear-cytoplasmic partitioning of PTEN and its regulation of nuclear and cytoplasmic Akt is a mechanism of carcinogenesis. To address our hypothesis, we propose to: 1: examine the role of nuclear PTEN in cellular functions and in the maintenance of cell cycle arrest; 2: determine the mechanism of nuclear PTEN localization; 3: evaluate the role of nuclear PTEN as a negative regulator of nuclear Akt activity and localization. When these studies complete, we will have a greater fundamental knowledge of the role of nuclear PTEN as a tumor suppressor in breast carcinogenesis. These data could also aid in drug development for breast cancer as well as provide novel targets for therapy and prevention.