The crosstalk between the PI3K/Akt signal and Skp2 in prostate cancer progression

描述（由申请人提供）：由于导致异常Akt活化的PTEN肿瘤抑制功能的丧失是人类癌症中的普遍事件并且与癌症转移相关，因此鉴定驱动癌症进展和转移的PTEN/PI 3 K/Akt途径下游的关键效应物是重要的。使用生物化学方法和小鼠遗传模型，我们确定Skp 2作为一个重要的Akt底物，在PTEN/Akt介导的肿瘤发生中起关键作用。Skp 2（S-phase kinase associated protein-2）是一种F-box蛋白，是Skp 2 SCF复合物中负责底物识别的E3连接酶组分。Skp 2过表达诱导细胞周期进入，p27的降解负责Skp 2介导的细胞周期进展。尽管Skp 2在许多人类癌症中过表达并与癌症转移相关，但仍不清楚Skp 2过表达在癌症进展期间如何发生以及其致癌活性如何调节。我们的研究首次提供了Akt激酶在S72处磷酸化Skp 2，Skp 2 S72磷酸化是协调Skp 2 E3连接酶活性和致癌功能的分子开关。本申请的目的是确定前列腺癌进展和转移中PTEN/PI 3 K/Akt信号和Skp 2 S72磷酸化之间的功能性串扰。本申请的中心假设是通过PI 3 K/Akt的Skp 2 S72磷酸化对于前列腺癌进展和转移是关键的。我们的中心假设是在我们强有力的初步数据的基础上形成的。这项研究的基本原理是，一旦Skp 2 S72磷酸化在前列腺癌进展和转移中的重要作用得到证实和确立，就可以实现更好的前列腺癌治疗或靶点。我们计划通过追求以下具体目标来测试我们的中心假设并实现本申请的目的：目的1）确定Skp 2基因表达和活性由PI 3 K/Akt途径调节的分子机制。目的2）探讨Skp 2 S72磷酸化在前列腺癌进展中的作用。目的3）探讨Akt和Skp 2在细胞迁移和侵袭中的功能交叉。目的4）探讨Skp 2及其S72磷酸化在前列腺癌转移中的作用。这项提案工作是创新的，因为它首次提供了Akt是Skp 2的激酶，并且Akt对Skp 2 S72的磷酸化对于Skp 2 E3连接酶活性、胞质定位和致癌功能至关重要。重要的是，我们的研究揭示了Skp 2是前列腺癌动物模型中PTEN/PI 3 K/Akt信号的关键下游效应子。随着受人尊敬的结果，该提案中的工作组合有望共同揭示Skp 2 S72磷酸化在前列腺癌进展和转移中的关键作用。这些结果将产生重要的积极影响，因此可能为前列腺癌治疗提供潜在的治疗靶点。我们的研究结果也将从根本上推进我们目前对前列腺癌如何发展并进一步发展到转移阶段的理解。

DESCRIPTION (provided by applicant): As loss of PTEN tumor suppressive function resulting in aberrant Akt activation is a prevalent event in human cancers and associated with cancer metastasis, it is important to identify the key effector downstream of the PTEN/PI3K/Akt pathway that drives cancer progression and metastasis. Using the biochemical approaches and mouse genetic models, we identified Skp2 as an important Akt substrate that plays a critical for PTEN/Akt-mediated tumorigenesis. Skp2 (S-phase kinase associated protein-2), an F-box protein, is an E3 ligase component of Skp2 SCF complex responsible for substrate recognition. Skp2 overexpression induces cell cycle entry, and the degradation of p27 is responsible for Skp2-mediated cell cycle progression. Although Skp2 is overexpressed in numerous human cancers and associates with cancer metastasis 1,2, it remains unclear how Skp2 overexpression occurs during cancer progression and how its oncogenic activity is regulated. Our study provides for the first time that Akt kinase phosphorylates Skp2 at S72 and Skp2 S72 phosphorylation is a molecular switch that orchestrates Skp2 E3 ligase activity and oncogenic functions. The objective of this application is to determine the functional crosstalk between PTEN/PI3K/Akt signal and Skp2 S72 phosphorylation in prostate cancer progression and metastasis. The central hypothesis of the application is that Skp2 S72 phosphorylation by PI3K/Akt is critical for prostate cancer progression and metastasis. Our central hypothesis has been formulated on the basis of our strong preliminary data. The rationale of the proposed research is that, once the important role of Skp2 S72 phosphorylation is confirmed and established in prostate cancer progression and metastasis, the better treatment or target for prostate cancer can be achieved. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following specific aims: Aim 1) To determine the molecular mechanism by which Skp2 gene expression and activity are regulated by the PI3K/Akt pathway. Aim 2) To determine the potential role of Skp2 S72 phosphorylation in prostate cancer progression. Aim 3) To determine the functional crosstalk between Akt and Skp2 in cell migration and invasion. Aim 4) To determine the potential role of Skp2 and Skp2 S72 phosphorylation in prostate cancer metastasis. This proposal work is innovative, because it provides for the first time that Akt is a kinase for Skp2 and that Skp2 S72 phosphorylation by Akt is critical for Skp2 E3 ligase activity, cytosolic localization, and oncogenic functions. Importantly, our study reveals that Skp2 is a critical downstream effector for the PTEN/PI3K/Akt signal in animal models of prostate cancers. With respected outcomes, the combination of work in this proposal is collectively expected to uncover the critical role Skp2 S72 phosphorylation in prostate cancer progression and metastasis. Such results will have an important positive impact and may therefore provide a potentially therapeutic target for prostate cancer treatment. Our results will also fundamentally advance our current understandings of how prostate cancer develops and further progresses into the metastasis stage.