ID PROTEIN FAMILY EXPRESSION AND FUNCTION IN PROSTATE CANCER

ID 蛋白家族在前列腺癌中的表达和功能

• 批准号: 7715356
• 负责人: JAIDEEP CHAUDHARY
• 金额: $ 18.92万
• 依托单位: CLARK ATLANTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715356
• 关键词: Androgen Receptor; Apoptosis; Cancer Biology; Cancer cell line; Carcinoma; Cell Cycle; Cell Proliferation; Computer Retrieval of Information on Scientific Projects Database; Cultured Tumor Cells; DU145; Differentiation Inhibitor; Disease Management; E-Cadherin; Epithelial; Family; Funding; Gene Expression; Genes; Grant; Helix-Turn-Helix Motifs; Heterogeneity; Human; Hypermethylation; Inhibitor of Differentiation Proteins; Institution; Invasive; Lead; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Methylation; Modeling; Mutation; Numbers; Oncogenes; PC3 cell line; Pathway interactions; Phenotype; Process; Prognostic Marker; Proliferating; Prostate; Protein Family; Proteins; Regulation; Reporting; Research; Research Personnel; Resources; Role; Source; TP53 gene; Telomerase; Testing; Tissues; Tumor Suppressor Proteins; Undifferentiated; United States National Institutes of Health; cell type; design; helix-loop-helix protein differentiation inhibitor; immortalized cell; loss of function; neoplastic cell; novel; promoter; protein function; receptor expression; therapeutic target; transcription factor; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The heterogeneity of prostate cancer suggests that the pathways that lead to malignant transformation are not uniform but certain genetic alterations and pathways may be common in the initiation leading to malignancy. The progression to invasive carcinoma is characterized by de-regulation of differentiation process, leading to an increase in the proliferation and a corresponding decrease in apoptosis. The transcription factor family, which is known to regulate both these processes, is the basic helix-loop-helix bHLH family. The Id (Inhibitor of differentiation) proteins function as natural negative regulators of bHLH protein activity through the formation of inactive heterodimers with bHLH transcription factors. Consequently, Id gene expression is elevated in undifferentiated, proliferating and tumor cells. The Id proteins also function at multiple levels and its interactions may not be limited to bHLH proteins. Over-expression of Id proteins results in apoptosis and/or cell proliferation. The ability of Id to stimulate the cell cycle, activate telomerase and immortalize cell types suggests that Id proteins may act as oncogenes or cooperating oncogenes. Our recent results suggest that the functions of Id proteins in prostate cancer cell lines are non-redundant. Id1, Id2 and Id3 are potential oncogenes or cooperating oncogenes and surprisingly, Id4 acts as a tumor suppressor. Id1 and Id3 target cell proliferation pathways, Id2 targets apoptosis and Id4 acts as a tumor suppressor by inducing the expression of p53, E-cadherin and androgen receptor (AR) in AR-ve prostate cancer cell line. Interestingly, Id3 copy number is also increased in DU145 prostate cancer cell line. Hence Id proteins represent a new paradigm in prostate cancer biology that needs to be carefully examined. Increased expression of Id1, Id2 and Id3 proteins has been reported in primary human tumors including human prostate and cultured tumor cells, whereas Id4 expression is lost in many cancer cell lines and tissues possibly due to promoter hypermethylation. Preliminary studies have demonstrated that loss of function of Id1/ Id3 and Id2 blocks proliferation and apoptosis respectively, whereas gain of Id4 functions initiates an epithelial phenotype and re-emergence of AR receptor expression in model prostate cancer cell lines. The present study is therefore designed to test the hypothesis that "Id genes (Id1, Id2, Id3 and Id4) have non-redundant functions and their expression levels, copy number changes (Id3) and promoter methylation status (id4) are sensitive prognostic markers strong therapeutic targets for the management of the disease". The novel ideas that are being pursued in this proposal are the copy number changes in Id3 and the role of Id4 as a tumor suppressor in prostate cancer.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 前列腺癌的异质性表明，导致恶性转化的途径并不统一，但某些基因改变和途径在导致恶性肿瘤的起始过程中可能是常见的。进展为浸润性癌的特点是分化过程失调，导致增殖增加和细胞凋亡相应减少。已知调节这两个过程的转录因子家族是基本的螺旋-环-螺旋 bHLH 家族。 Id（分化抑制剂）蛋白通过与 bHLH 转录因子形成无活性异二聚体，充当 bHLH 蛋白活性的天然负调节因子。因此，Id 基因表达在未分化细胞、增殖细胞和肿瘤细胞中升高。 Id 蛋白还在多个水平上发挥作用，其相互作用可能不限于 bHLH 蛋白。 Id蛋白的过度表达导致细胞凋亡和/或细胞增殖。 Id 刺激细胞周期、激活端粒酶和永生化细胞类型的能力表明，Id 蛋白可能充当癌基因或协同癌基因。我们最近的结果表明，前列腺癌细胞系中 Id 蛋白的功能是非冗余的。 Id1、Id2 和 Id3 是潜在癌基因或协同癌基因，令人惊讶的是，Id4 充当肿瘤抑制因子。 Id1 和 Id3 靶向细胞增殖途径，Id2 靶向细胞凋亡，Id4 通过诱导 AR-ve 前列腺癌细胞系中 p53、E-钙粘蛋白和雄激素受体 (AR) 的表达作为肿瘤抑制因子。 有趣的是，DU145 前列腺癌细胞系中的 Id3 拷贝数也有所增加。 因此，Id 蛋白代表了前列腺癌生物学的一个新范例，需要仔细检查。 据报道，在原发性人类肿瘤（包括人前列腺和培养的肿瘤细胞）中 Id1、Id2 和 Id3 蛋白的表达增加，而 Id4 表达在许多癌细胞系和组织中丢失，可能是由于启动子高甲基化。 初步研究表明，Id1/Id3 和 Id2 功能的丧失分别会阻止增殖和凋亡，而 Id4 功能的获得会启动模型前列腺癌细胞系中的上皮表型和 AR 受体表达的重新出现。因此，本研究旨在检验以下假设：“Id基因（Id1、Id2、Id3和Id4）具有非冗余功能，其表达水平、拷贝数变化（Id3）和启动子甲基化状态（id4）是敏感的预后标志物控制疾病的强有力的治疗目标”。 该提案所追求的新想法是 Id3 的拷贝数变化以及 Id4 作为前列腺癌肿瘤抑制因子的作用。