ID PROTEIN FAMILY EXPRESSION AND FUNCTION IN PROSTATE CANCER

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 前列腺癌的异质性表明，导致恶性转化的途径并不一致，但某些遗传改变和途径可能在导致恶性肿瘤的起始中是常见的。向浸润性癌的进展的特征在于分化过程的失调，导致增殖的增加和凋亡的相应减少。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的异源二聚体而作为bHLH蛋白活性的天然负调节剂起作用。因此，Id基因表达在未分化、增殖和肿瘤细胞中升高。Id蛋白也在多个水平起作用，并且其相互作用可能不限于bHLH蛋白。Id蛋白的过表达导致细胞凋亡和/或细胞增殖。 Id刺激细胞周期、激活端粒酶和使细胞类型永生化的能力表明Id蛋白可能作为癌基因或协同癌基因。我们最近的研究结果表明，前列腺癌细胞系中Id蛋白的功能是非冗余的。 Id 1、Id 2和Id 3是潜在的癌基因或协同癌基因，并且令人惊讶的是，Id 4充当肿瘤抑制基因。在AR-ve前列腺癌细胞系中，Id 1和Id 3靶向细胞增殖途径，Id 2靶向细胞凋亡，Id 4通过诱导p53、E-cadherin和雄激素受体（AR）的表达而作为肿瘤抑制剂。 有趣的是，在DU 145前列腺癌细胞系中Id 3拷贝数也增加。 因此，Id蛋白代表了前列腺癌生物学的新范式，需要仔细研究。 Id 1、Id 2和Id 3蛋白的表达增加已在包括人前列腺和培养的肿瘤细胞的原发性人类肿瘤中报道，而Id 4表达在许多癌细胞系和组织中丢失，可能是由于启动子超甲基化。 初步研究表明，Id 1/Id 3和Id 2功能的丧失分别阻断增殖和凋亡，而Id 4功能的获得启动上皮表型和模型前列腺癌细胞系中AR受体表达的重新出现。因此，本研究旨在验证“Id基因（Id 1，Id 2，Id 3和Id 4）具有非冗余功能，其表达水平，拷贝数变化（Id 3）和启动子甲基化状态（Id 4）是敏感的预后标志物，是疾病管理的强治疗靶点”的假设。 该提案中正在追求的新想法是Id 3的拷贝数变化和Id 4作为前列腺癌肿瘤抑制因子的作用。

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.