Androgen Control of TGF-beta signaling

雄激素对 TGF-β 信号传导的控制

• 批准号: 6774391
• 负责人: DAVID DANIELPOUR
• 金额: $ 29.91万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-02 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774391
• 关键词: androgen receptor; androgens; apoptosis; biological signal transduction; cell growth regulation; cell line; dihydrotestosterone; enzyme linked immunosorbent assay; flow cytometry; gel mobility shift assay; gene expression; genetic transcription; growth inhibitors; hormone regulation /control mechanism; matrix assisted laser desorption ionization; microarray technology; neoplastic growth; prostate neoplasms; protein protein interaction; receptor binding; transfection; transforming growth factors; tumor suppressor proteins; western blottings

DESCRIPTION (provided by applicant): Transforming growth factor-betas (TGF-betas) are 25 kDa multifunctional autocrine/paracrine peptides with potent activity on growth suppression and apoptosis of epithelial cells. In the prostate, expression of TGF-beta protein and their receptors are induced upon androgen ablation, coincident with apoptotic cell death that occurs concomitantly in this tissue. Prostatic cells lose dependence on androgens and become resistant to TGF-beta responses during carcinogenesis, through mechanisms that remain to be defined. Further support for a tumor suppressor role of TGF-beta in the prostate comes from studies where we ablated TGF-beta signaling in two non-tumorigenic cell lines (NRP-152 and DP-153) by retroviral transduction of a dominant-negative TbetaRII, and showed the consequent loss of response to TGF-beta triggers malignant transformation. Loss of TGF-beta receptor expression is one of many potential mechanisms of TGF-beta resistance. Other pathways may involve activation of certain oncogenes that intercept TGF-beta signals at various levels. We have recently reported that DHT can directly block TGF-beta signaling through an association between AR and Smad3, leading to the transcriptional inactivation of Smad3 in LNCaP and NRP-154 prostatic epithelial cells. We provide evidence using EMSAs that AR's inhibitory effect is through blocking the binding of Smad3 to Smad Binding Elements (SBE) of target genes. Here we propose to investigate:1) the effects of DHT/AR on growth arrest and apoptosis induced by TGF-beta (or active Smad3), 2) expression of TGF-beta inducible genes by DHT/AR, 3) the structure/functional basis behind the binding of AR to Smad3, 4) possible function of AR co-activators as co-regulators or Smad3 through AR, and 5) differences in the interaction of AR with Smad3 in various nontumorigenic and tumorigenic cell lines. We believe these studies will most certainly impact on the therapeutic intervention of prostate cancer.

描述（由申请方提供）：转化生长因子-β（TGF-β）是25 kDa多功能自分泌/旁分泌肽，对上皮细胞的生长抑制和凋亡具有强效活性。在前列腺中，TGF-β蛋白及其受体的表达在雄激素消融后被诱导，与该组织中伴随发生的凋亡性细胞死亡一致。前列腺细胞失去对雄激素的依赖性，并在癌变过程中对TGF-β反应产生抗性，其机制仍有待确定。对TGF-β在前列腺中的肿瘤抑制作用的进一步支持来自于我们通过显性阴性TbetaRII的逆转录病毒转导来消除两种非致瘤细胞系（NRP-152和DP-153）中的TGF-β信号传导的研究，并且显示随后对TGF-β的应答丧失触发恶性转化。TGF-β受体表达的丧失是TGF-β抗性的许多潜在机制之一。其他途径可能涉及某些癌基因的激活，这些癌基因在不同水平上拦截TGF-β信号。我们最近报道，DHT可以通过AR和Smad3之间的关联直接阻断TGF-β信号传导，导致LNCaP和NRP-154前列腺上皮细胞中Smad3的转录失活。我们使用EMSA提供证据表明，AR的抑制作用是通过阻断Smad3与靶基因的Smad结合元件（SBE）的结合。本研究拟探讨：1）DHT/AR对TGF-β（或活性Smad3）诱导的生长停滞和细胞凋亡的影响; 2）DHT/AR对TGF-β诱导基因的表达; 3）AR与Smad3结合的结构/功能基础; 4）AR共激活因子作为Smad3的共调节因子的可能功能; 5）AR与Smad3在各种非致瘤性和致瘤性细胞系中相互作用的差异。我们相信这些研究肯定会对前列腺癌的治疗干预产生影响。