BH3-only protein BNIP3 in tumor progression

BH3-only 蛋白 BNIP3 在肿瘤进展中的作用

• 批准号: 6957117
• 负责人: GOVINDASWAMY CHINNADURAI
• 金额: $ 12.64万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6957117
• 关键词: BCL2 gene /protein; acidity /alkalinity; athymic mouse; biological signal transduction; breast neoplasms; carcinoma; cell line; gene expression; human genetic material tag; hypoxia; laboratory mouse; lung neoplasms; mitochondria; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic cell; neoplastic process; transcription factor; xenotransplantation

DESCRIPTION (provided by applicant): BNIP3 is a BH3-only BCL-2 family mitochondrial protein. Overexpression of BNIP3 causes mitochondrial dysfunction and a slow necrosis-type of cell death. The expression of the Bnip3 gene is activated in hypoxic microenvironments and is a direct target for the transcription factor HIF-1. Expression of Bnip3 is associated with high-grade invasive tumors of the breast and lung. Our hypothesis suggests that chronic overexpression of Bnip3 in a hypoxic and acidic tumor microenvironment results in the evolution of aggressive tumor cells. We will test this hypothesis in the mouse xenotransplant model of human lung and mammary carcinoma cell lines. Our hypothesis also predicts that BNIP3-induced mitochondrial dysfunction activates the retrograde mitochondrial signaling pathway resulting in activation of expression of markers associated with tumor invasion and survival. We propose to determine the effects of BNIP3 expression on mitochondrial signaling molecules and effector nuclear transcription factors. The role of the mitochondrial signaling pathway in BNIP-3-induced tumor progression will be determined by the use of dominant negative inhibitors of the pathways. Our proposed project will provide support for a new concept that chronic overexpression of a death-promoting molecule in hypoxic solid tumors may lead to the evolution of tumor aggressiveness and progression. Our results may also provide the experimental support to suggest that BNIP3 may be a new prognostic marker for human cancer.

描述（由申请人提供）：BNIP3 是一种仅包含 BH3 的 BCL-2 家族线粒体蛋白。 BNIP3 的过度表达会导致线粒体功能障碍和缓慢坏死型细胞死亡。 Bnip3 基因的表达在缺氧微环境中被激活，并且是转录因子 HIF-1 的直接靶标。 Bnip3 的表达与乳腺和肺部的高级侵袭性肿瘤相关。我们的假设表明，Bnip3 在缺氧和酸性肿瘤微环境中的长期过度表达会导致侵袭性肿瘤细胞的进化。我们将在人肺癌和乳腺癌细胞系的小鼠异种移植模型中检验这一假设。我们的假设还预测 BNIP3 诱导的线粒体功能障碍会激活逆行线粒体信号通路，从而激活与肿瘤侵袭和存活相关的标记物的表达。我们建议确定 BNIP3 表达对线粒体信号分子和效应核转录因子的影响。线粒体信号通路在 BNIP-3 诱导的肿瘤进展中的作用将通过使用该通路的显性失活抑制剂来确定。我们提出的项目将为一个新概念提供支持，即缺氧实体瘤中促死亡分子的长期过度表达可能导致肿瘤侵袭性和进展的演变。我们的结果也可能为表明 BNIP3 可能成为人类癌症的新预后标志物提供实验支持。