Evaluation of PI3K pathway and p110 in prostate cancer

近年来研究发现，前列腺中常见的抑癌基因PTEN是PI 3激酶通路的关键调节因子。PTEN蛋白是一种磷酸酶，除了其对蛋白质底物的活性外，还可以使PI 3激酶家族的脂质产物去磷酸化。PTEN去除3 '-磷酸，这是在PI 3激酶家族成员的产物中唯一发现的。对PTEN基因的分析表明，这种PI 3磷酸酶活性对其肿瘤抑制功能是必不可少的。由于这些脂质是介导细胞生长和存活的中枢信号传导途径的中枢介质，因此假设PTEN功能的丧失应增加生长和存活。所有这些兴奋点都指出了需要研究人类前列腺肿瘤中的PI 3激酶信号传导，并生成模型系统以允许研究动物前列腺肿瘤中的PI 3激酶通路。在这项研究中，我们将创建单克隆抗血清，以研究实际肿瘤样本中关键PI 3激酶通路成员的激活状态。此外，我们还将建立小鼠模型，以测试PI 3激酶的p110催化亚基在小鼠前列腺癌模型中的作用。此外，我们将通过产生转基因小鼠来产生小鼠模型，该小鼠模型测试p110激酶的作用对于前列腺肿瘤形成是足够的，在该转基因小鼠中，p110的活化突变等位基因通过仅在前列腺组织中有活性的probasin表达。我们还将测试Pi 3激酶活性是否是小鼠中PTEN介导的肿瘤形成所必需的。为此，我们将产生p110基因的loxed版本，其将允许我们敲除前列腺中的Pi 3激酶功能，所述前列腺已被工程化以以PTEN依赖性方式发展前列腺肿瘤。

Recently PTEN, a tumor suppressor gene commonly mutant in prostate, has been demonstrated to be a key regulator of the PI3 kinase pathway. The PTEN protein is a phosphatase which, in addition its activity against protein substrates, can dephosphorylate the lipid products of the PI3 kinase family. PTEN removes the 3'-phosphate, which is the found uniquely in the products of PI3 kinase family members. Genetic analyses of PTEN suggest that this PI3 phosphatase activity is ess3ential to its tumor suppressor function. Since these lipids are, among other things, central mediators of central signaling pathways which mediate both cell growth and survival, it is hypothesized that loss of PTEN function should increase both growth and survival. All this excitement has pointed out the need to study PI3 kinase signaling in human prostate tumors and to generate model systems to allow study of the PI3 kinase pathway in prostate tumors in animals. In this grant we will create monoclonal antisera to study the activation state of key PI3 kinase pathway members in actual tumor samples. In addition we will generate mouse models which test the role of the p110 catalytic subunit of PI3 kinase in mouse prostate cancer models. In addition we will generate mouse models which test the role of the p110 kinase is sufficient for prostate tumor formation by generating a transgenic mouse in which an activated mutant allele of p110 is expressed via the probasin which is only active in prostate tissue. We will also test if Pi3 kinase activity is necessary for PTEN mediated tumor formation in mice, To do this we will generate a loxed version of the p110 gene which will allow us to knock out Pi3 kinase function in the prostates which have been engineered to develop prostate tumors in a PTEN dependent fashion.