bHLH Transcription Factors in Prostate Cancer Malignancy

前列腺癌恶性肿瘤中的 bHLH 转录因子

基本信息

批准号：
7222000
负责人：
CYNTHIA M SMAS
金额：
$ 24.81万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-11 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7222000
关键词：
Ablation Address Androgens BHLH Protein Binding Biological Assay Cancerous Cell Line Cells Complex DNA Binding DU145 Data Development Diagnosis Differentiation and Growth Disease Dominant-Negative Mutation E protein Ectopic Expression Epithelial Epithelial Cells Family Gene Expression Gene Targeting Genes Helix-Turn-Helix Motifs Heterodimerization Hybridization Array In Vitro Intervention LNCaP Lead Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Modeling Molecular Molecular Profiling Numbers PC3 cell line Pathway interactions Pattern Process Prostate Prostatic Diseases Protein Binding Protein Overexpression Proteins Refractory Disease Regulation Research Resistance Reverse Transcriptase Polymerase Chain Reaction Role Screening procedure Signal Pathway Signal Transduction System Tetracycline Tetracyclines Therapeutic Intervention Tissues Two-Hybrid System Techniques Up-Regulation Variant Work Yeasts base cancer cell cancer diagnosis cell type helix-loop-helix protein differentiation inhibitor in vivo in vivo Model inhibitor/antagonist member men novel protein expression tumor tumor progression tumorigenesis tumorigenic yeast two hybrid system

项目摘要

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见的恶性肿瘤，雄激素消融疗法是治疗的主要过程。在许多情况下，该疾病发展为抗雄激素的状态，为此，几乎没有可行的治疗选择。阐明该过程的分子步骤可以鉴定出新的治疗干预点。我们最近确定了DNA结合的抑制剂ID1是转录调节剂的螺旋 - 环螺旋（HLH）家族的成员，在雄激素依赖性，侵略性的LNCAP人前列腺细胞中被下调，但在其雄激素独立方面表达。它也在雄激素独立的DU145和PC3细胞中表达。此外，ID1在人类前列腺癌中过表达。这支持了以下假设：在侵略性前列腺癌细胞中，ID1复合物具有各种螺旋环螺旋（BHLH）结合伙伴以改变转录活性，从而最终导致了增强的恶性肿瘤和促进向雄激素独立性的过渡。拟议的工作详细介绍了ID1，其E蛋白结合伴侣的功能作用以及前列腺癌恶性肿瘤中的其他BHLH因子的功能作用：1。1.）表达模式和调节BHLH因子，其相互作用的蛋白质和靶基因在体外和前列腺恶性症模型中的相互作用蛋白和靶基因。 2.）通过使用四环素调节的表达系统改变BHLH因子的水平，这些蛋白质对前列腺细胞恶性肿瘤的影响将通过体外和体内分析确定。预计ID1的过表达将增加恶性肿瘤，而通过减轻ID1的肿瘤效应的异位表达将降低恶性肿瘤。 3.）ID1和E蛋白BHLH蛋白在前列腺中的途径将通过ID1和E12结合伴侣的酵母筛查鉴定，并通过抑制性减法杂交和基于阵列的ID1和E蛋白靶基因分析。 ID基因和BHLH因子可能是为晚期前列腺癌开发新疗法的合适靶标。