BCL2 GENE FAMILY, APOPTOSIS RESISTANCE AND BREAST CANCE

描述：（改编自研究者摘要）长期 目标和健康相关性：他们的研究重点是 了解对p53非依赖性细胞凋亡的抗性的发展 有助于乳腺癌的发展。 程序化细胞激活 发展中的癌症中的死亡或细胞凋亡延缓了肿瘤的进展。 一些抗癌治疗通过诱导细胞凋亡来减小肿瘤大小。 的 该建议的目的是确定bcl-2的简单过表达是否 家庭成员“生存诱导物”与“死亡诱导物”相比， 乳腺癌患者对p53非依赖性凋亡的抵抗机制 恶性转化 Bcl-2家族成员存活和死亡诱导物 通过形成同源和异源二聚体介导细胞凋亡。 这 这导致了这样一种假设，即细胞命运直接由 相对丰富的生存和死亡诱导物。 研究设计：A 乳腺癌转基因小鼠模型，其中诱导 p53非依赖性细胞凋亡（WAP-Tag）将与 建立过表达bcl-2或bcl-xlong（bcl-xL）的转基因株系， 在乳腺中。 bcl-2的表达受WAP的调控 启动子 bcl-xL的表达将使用 四环素反应基因表达系统。 腺病毒载体将 用于在转基因小鼠乳腺中表达bcl-xshort（bcl-xS）， 将小鼠置于器官培养物中。 具体目标：1. 测试是否简单 与Tag联合的存活诱导物bcl-2或bcl-xL的过表达 导致对p53非依赖性细胞凋亡的立即抗性。 比较 bc 1-xL和bcl-2过度表达的结果。 2. 分析频率 当死亡诱导物bcl-xS在组织中表达时， 对p53非依赖性细胞凋亡敏感或抵抗。 3. 确定 如果在肿瘤发生过程中bcl-2或bcl-xL与Tag的过表达改变了 bcl-2相关基因或非bcl-2基因的表达模式或水平 凋亡相关基因。 4. 确定bcl-2是否过度表达 bcl-xL影响其他已知的细胞基因的表达模式， 在Tag诱导的乳腺癌中差异表达。 5. 建立 bcl-2相关基因表达异常的生物学意义 乳腺肿瘤发生中的基因。

DESCRIPTION: (adapted from the investigator's abstract) Long term objectives and health relatedness: Their research is focused on understanding how development of resistance to p53-independent apoptosis contributes to progression of breast cancer. Activation of programmed cell death or apoptosis within a developing cancer retards tumor progression. Some anti-cancer treatments reduce tumor size by inducing apoptosis. The aim of this proposal is to determine if simple overexpression of bcl-2 family member 'survival inducers' as compared to 'death inducers' is a mechanism of resistance to p53-independent apoptosis in breast undergoing malignant transformation. Bcl-2 family member survival and death inducers mediate apoptosis through the formation of homo- and hetero-dimers. This leads to the hypothesis that cell fate is determined directly by the relative abundance of survival and death inducers. Research Design: A transgenic mouse model of breast cancer in which induction of p53-independent apoptosis (WAP-Tag) will be used in conjunction with established transgenic lines which overexpress bcl-2 or bcl-xlong (bcl-xL) in the mammary gland. Expression of bcl-2 will be controlled by the WAP promoter. Expression of bcl-xL will be conditionally controlled using the tetracycline responsive gene expression system. An adenovirus vector will be used to express bcl-xshort (bcl-xS) in mammary glands from transgenic mice placed in organ culture. Specific aims: 1. Test if simple overexpression of survival inducers bcl-2 or bcl-xL in conjunction with Tag results in immediate resistance to p53-independent apoptosis. Compare results of bc1-xL and bcl-2 overexpression. 2. Analyze the frequency of apoptosis when the death inducer bcl-xS is expressed in tissue which is either sensitive or resistant to p53-independent apoptosis. 3. Determine if overexpression of bcl-2 or bcl-xL with Tag during tumorigenesis alters the pattern or levels of expression of bcl-2 related genes or non-bcl-2 related apoptosis pathway genes. 4. Determine if overexpression of bcl-2 and bcl-xL influences expression patterns of other cellular genes known to be differentially expressed in Tag induced breast cancers. 5. Establish the biological significance of dysregulated expression of bcl-2 related genes in breast tumorigenesis.