P13K/PTEN/Akt (PKB), Signaling and genesis of cancer

描述（申请人提供）：PI 3-激酶/PTEN/Akt（PKB）信号传导 最近出现的途径是最经常被废除的途径之一， 在人类癌症中的通路。PI 3-激酶及其下游效应子， 丝氨酸/苏氨酸激酶Akt，具有致癌活性， 是一种肿瘤抑制因子PTEN经常失活 通过人类癌症中的PTEN缺失或突变以及人类癌症中的PTEN杂合缺失， 小鼠诱导不同类型的肿瘤。到目前为止， PTEN失活主要归因于Akt活性的升高。我们 长期目标是了解Akt的组成性激活是如何 在细胞和生物体水平上都有助于癌症的发生。我们有 以前的研究表明Akt促进细胞存活并阻断细胞凋亡 由多种凋亡刺激诱导，并且还诱导蛋白质合成。 虽然Akt的这些和其他已知的活性可能有助于其致癌作用， 可能它们不足以使Akt发挥其致癌功能。 在这个提议中，我们打算调查Akt作为调节剂的新活动 DNA损伤诱导的G2/M检查点。我们发现了这种活动， 表达活化Akt的细胞对暴露于6-硫代鸟嘌呤具有抗性， （6-TG）并绕过γ射线和6-TO诱导的G2/M期阻滞。这 Akt的活性，其独立于其抗凋亡活性， 独立于p53，可能是其致癌功能的关键决定因素。 我们认为Akt的抗凋亡活性与其在细胞凋亡中的作用有关。 绕过G2/M检查点的能力可导致细胞持续增殖 尽管基因组的完整性被破坏了我们还将确定 通过将PTEN+/-小鼠杂交至 Akt敲除小鼠。我们已经破坏了小鼠的akt-1基因， 这些小鼠与PTEN +/-小鼠一起产生PTEN+/-/Aktl-/-小鼠。的要求 还将确定Akt在其他小鼠模型中的癌症发生的作用。 最后，由于前列腺癌中Akt的频繁激活，我们将 重点研究其在前列腺癌中的作用， 显性阴性Akt对小鼠前列腺的作用。 本提案中提出的研究将对以下方面产生重大影响： 确定有效的癌症治疗，因为许多目前的治疗 策略依赖于诱导DNA错配修复和G2/M检查点 导致细胞凋亡。

DESCRIPTION (PROVIDED BY APPLICANT): The PI 3-kinase/PTEN/Akt(PKB) signaling pathway has been recently emerged as one of the most frequently abrogated pathway in human cancer. Both PI 3-kinase and its downstream effector, the serine/threonine kinase Akt, posses oncogenic activity whereas PTEN that negates their activities is a tumor suppressor. PTEN is frequently inactivated by deletion or mutations in human cancer and heterozygous deletion of PTEN in mice induces diverse types of tumors. Thus far, the tumorigenic consequence of PTEN inactivation has been mostly attributed to elevation of Akt activity. Our long-term goal is to understand how does constitutive activation of Akt contribute to genesis of cancer at both cellular and organism levels. We have previously demonstrated that Akt promotes cell survival and blocks apoptosis induced by a variety of apoptotic stimuli and also induces protein synthesis. While these and other known activities of Akt may contribute to its oncogenic potential they may not be sufficient for Akt to exert its oncogenic function. In this proposal we intend to investigate a new activity of Akt as a regulator of DNA damage-induced G2/M checkpoint. We discovered this activity by showing that cells expressing activated Akt are resistant to exposure to 6-thioguanine (6-TG) and bypass the G2/M arrest induced by gamma-irradiation and 6-TO. This activity of Akt, which is independent of its anti-apoptotic activity and independent of p53, may be a critical determinant of its oncogenic function. We propose that the anti-apoptotic activity of Akt in conjunction with its ability to bypass G2/M checkpoint can lead to continuos cellular proliferation despite disruption of genome integrity. We will also determine the requirement of Akt for PTEN+/- induced tumorigenesis in mice by crossing PTEN+/- mice to Akt null mice. We have already disrupted the akt-1 gene in mice and crossed these mice with PTEN +/- mice to generate PTEN+/-/Aktl-/- mice. The requirement of Akt for the genesis of cancer in other mice models will be also determined. Finally, because of the frequent activation of Akt in prostate cancer we will focus on studying its role in prostate cancer by targeting activated Akt and dominant negative Akt to the mouse prostate. The studies presented in this proposal will have strong implications on determination of effective cancer therapy because many current therapy strategies rely on the induction of DNA mismatch repair, and G2/M checkpoint that lead to apoptosis.