Pten-loss Dysregulated Pathways in Prostate Cancer

前列腺癌中 Pten 丢失失调通路

基本信息

批准号：
7938940
负责人：
Zhenbang Chen
金额：
$ 36.63万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7938940
关键词：
1-Phosphatidylinositol 3-Kinase Acute Address Adenocarcinoma African American Age-Months Age-Years American Androgens Award Cancer Etiology Castration Caucasians Caucasoid Race Cell Aging Cell Line Cessation of life Characteristics Data Employee Strikes Ethnic group Event Genes Goals Growth Human In Vitro Incidence Knockout Mice Link Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Molecular Morbidity - disease rate Mus Mutant Strains Mice Mutate Mutation Oncogenic PTEN gene Pathway interactions Phosphoric Monoester Hydrolases Phosphotransferases Prostate Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Protein p53 Race Recurrent tumor Refractory Regulation Resistance Role Serine Specificity Stress TP53 gene Testing Transgenic Mice Tumor Suppressor Genes Up-Regulation androgen independent prostate cancer cancer health disparity in vivo insight men mortality mouse model novel oncoprotein p21 overexpression p19ARF response tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by the applicant): Prostate Cancer (PCa) is the second leading cause of cancer-related deaths (after lung cancer) in American men, and the morbidity and the mortality to PCa are even higher in African American men as compared Caucasians. Molecular mechanisms leading to the initiation and progression of PCa including castration resistant prostate cancer (CRPC) or androgen insensitive prostate cancer (AI-PC) are poorly understood. PTEN and p53 are the two most frequently deleted and/ or mutated genes in a variety of human cancers including advanced PCa. Loss of PTEN leads to the hyperactivation of phosphatidylinositol-3-OH kinase (PI3K) and serine/Thr kinase (Akt/PKB). Pten-deficient mice develop high grade prostatic intraepithelial neoplasia (HGPIN) and invasive adenocarcinoma. We have recently demonstrated in our mouse model that the acute inactivation of Pten unexpectedly elicits cellular senescence, a novel mechanism suppressing cancer progression. Aberrant regulation of oncogenes and tumor suppressors including p19Arf, p53 and p21 proteins have been observed in prostate tumors of Pten-deficient mice. We hypothesize that aberrant activation of p19Arf-p53 pathways cooperates with Pten loss to result in prostate cancer progression. We propose to test this hypothesis and to study the molecular mechanisms of regulating Pten-p19Arf-p53 network in prostate cancer using mouse models and cell lines with following Specific Aims: 1) To define the role of p19Arf in prostate cancer progression. 2) To determine the functional roles of p19Arf in the crosstalk of Pten and p53 during tumorigenesis. 3) To address the consequence and relevance of p19Arf inactivation in CRPC growth using Pten/p53 mouse model. Results obtained from this award will provide us valuable insights into novel roles of ARF in prostate cancer progression.

描述（由申请人提供）：前列腺癌（PCA）是美国男性中与癌症相关死亡的第二大原因（仅次于肺癌），而在非洲裔美国男性中，与高加索人相比，对PCA的发病率和死亡率甚至更高。鲜为人知的是，导致PCA引起和进展的分子机制，包括抗cast割前列腺癌（CRPC）或雄激素不敏感的前列腺癌（AI-PC）。 PTEN和P53是包括晚期PCA在内的各种人类癌症中最常删除和/或突变的基因。 PTEN的丧失导致磷脂酰肌醇-3-OH激酶（PI3K）和丝氨酸/THR激酶（AKT/PKB）的过度激活。缺乏PTEN的小鼠会发展出高级前列腺上皮内肿瘤（HGPIN）和浸润性腺癌。最近，我们在小鼠模型中证明了PTEN的急性失活意外引起细胞衰老，这是一种抑制癌症进展的新机制。在PTEN缺陷型小鼠的前列腺肿瘤中，已经观察到对癌基因和肿瘤抑制剂的异常调节。我们假设p19arf-p53途径的异常激活与PTEN损失合作，从而导致前列腺癌的进展。我们建议使用小鼠模型和细胞系在前列腺癌中调节PTEN-P19ARF-P53网络的分子机制，并研究以下特定目的：1）定义P19ARF在前列腺癌进展中的作用。 2）确定p19arf在肿瘤发生过程中P19ARF在PTEN和p53的串扰中的功能作用。 3）使用PTEN/p53小鼠模型解决P19ARF灭活在CRPC生长中的结果和相关性。从该奖项获得的结果将为我们提供对ARF在前列腺癌进展中新作用的新作用的宝贵见解。