bHLH Transcription Factors in Prostate Cancer Malignancy

前列腺癌恶性肿瘤中的 bHLH 转录因子

• 批准号: 7087029
• 负责人: CYNTHIA M SMAS
• 金额: $ 25.55万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-11 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087029
• 关键词: androgens; biological signal transduction; cell line; clinical research; gene expression; genetic regulation; human tissue; neoplastic growth; polymerase chain reaction; prostate neoplasms; protein structure function; tissue /cell culture; transcription factor; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed malignancy in men and androgen ablation therapy is the main course of treatment. In many cases the disease progresses to an androgen-resistant state, for which there are few viable treatment options. Elucidation of the molecular steps of this process may identify novel points of therapeutic intervention. We have recently determined that the inhibitor of DNA binding, Id1, a member of the helix-loop-helix (HLH) family of transcriptional regulators, is downregulated in androgen-dependent, less aggressive LNCaP human prostate cells but expressed in their androgen-independent counterparts. It is also expressed in androgen-independent DU145 and PC3 cells. Moreover, Id1 is overexpressed in human prostate cancer. This supports the hypothesis that in aggressive prostate cancer cells Id1 complexes various helix-loop-helix (bHLH) binding partners to alter transcriptional activity, with an end result of promoting increased malignancy and facilitating transition to androgen independence. The proposed work addresses in detail the functional role of Id1, its E-protein binding partners, and other bHLH factors in prostate cancer malignancy with the following specific aims: 1.) The expression pattern and regulation bHLH factors, their interacting proteins and target genes in in vitro and in vivo models of prostate malignancy. 2.) By altering the levels of bHLH factors using a tetracycline-regulated expression system, the impact of these proteins on prostate cell malignancy will be determined by in vitro and in vivo assays. Overexpression of Id1 is predicted to increase malignancy while ectopic expression of E12 by alleviating the tumorigenic effects of Id1, is predicted to decrease malignancy. 3.) Pathways of Id1 and E-protein bHLH protein action in prostate will be identified by yeast two hybrid screening for Id1 and E12 binding partners and with suppressive subtractive hybridization and array-based analysis of Id1 and E-protein target genes. Id genes and bHLH factors may be suitable targets for development of new treatments for advanced prostate cancer.

描述（由申请人提供）：前列腺癌是男性最常诊断的恶性肿瘤，雄激素消融疗法是主要治疗方法。在许多情况下，疾病会发展到雄激素抵抗状态，对此几乎没有可行的治疗选择。阐明这一过程的分子步骤可能会确定治疗干预的新点。我们最近确定，DNA 结合抑制剂 Id1 是转录调节因子螺旋-环-螺旋 (HLH) 家族的成员，在雄激素依赖性、侵袭性较低的 LNCaP 人类前列腺细胞中下调，但在雄激素非依赖性细胞中表达。它还在不依赖雄激素的 DU145 和 PC3 细胞中表达。此外，Id1 在人类前列腺癌中过度表达。这支持了这样的假设：在侵袭性前列腺癌细胞中，Id1 与各种螺旋-环-螺旋 (bHLH) 结合伴侣形成复合物以改变转录活性，最终结果促进恶性程度增加并促进向雄激素独立性的转变。拟议的工作详细阐述了 Id1、其 E 蛋白结合伴侣和其他 bHLH 因子在前列腺癌恶性肿瘤中的功能作用，具体目标如下：1.) 前列腺恶性肿瘤体外和体内模型中 bHLH 因子、它们的相互作用蛋白和靶基因的表达模式和调节。 2.)通过使用四环素调节的表达系统改变bHLH因子的水平，将通过体外和体内测定来确定这些蛋白质对前列腺细胞恶性肿瘤的影响。 Id1 的过度表达预计会增加恶性肿瘤的发生，而 E12 的异位表达则通过减轻 Id1 的致瘤作用预计会减少恶性肿瘤的发生。 3.) Id1 和 E 蛋白 bHLH 蛋白在前列腺中的作用途径将通过 Id1 和 E12 结合配偶体的酵母二杂交筛选以及 Id1 和 E 蛋白靶基因的抑制性消减杂交和基于阵列的分析来鉴定。 Id 基因和 bHLH 因子可能是开发晚期前列腺癌新疗法的合适靶标。