Cyclin D1: repercussions of AR control and alternative splicing in prostate cance

Cyclin D1：AR 控制和选择性剪接对前列腺癌的影响

基本信息

批准号：
7667043
负责人：
KAREN E KNUDSEN
金额：
$ 26.84万
依托单位：
THOMAS JEFFERSON UNIVERSITY
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：
2003-06-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7667043
关键词：
Ablation Alternative Splicing Androgen Receptor Androgens Apoptosis Attenuated Binding Biological Assay Cell Cycle Cell Cycle Arrest Cells Chromatin Cyclin D1 Cyclin-Dependent Kinase 4 Cyclins Cytoplasm Data Dependence Development Disease Employee Strikes Environment Feedback Funding G1 Phase Gene Activation Gene Expression Gene Expression Regulation Gene Targeting Goals Growth Growth and Development function Histones Human In Vitro Lesion Ligands Malignant Neoplasms Malignant neoplasm of prostate Mediating Modeling Molecular Oncogenic Pathway interactions Phase Transition Premalignant Process Prostate Protein Isoforms Proteins Publishing RNA Splicing Receptor Cell Recurrence Recurrent disease Recurrent tumor Regulation Relative (related person)Repression Role Specificity Testosterone Therapeutic Intervention Tissue Recombination Transcription Repressor/Corepressor Transcriptional Regulation Transgenic Model Variant Xenograft Model base cancer cell in vivo novel public health relevance receptor function response transcription factor tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCa) cells are dependent on androgen receptor (AR) function for growth and survival; this dependence is exploited in treatment of disseminated cancers, wherein ablation of AR activity is the first line of therapeutic intervention. While initially effective, recurrent tumors ultimately arise as a result of inappropriately restored AR function. AR is a master regulator of G1-S phase transitions in PCa, and interrogation of this mechanism led to the discovery of significant cross-talk mechanisms between the AR and cell cycle pathways. Cyclin D1 is a major effector of androgen action, and serves specialized functions in PCa that were delineated during the first funding period. Active AR induces cyclin D1 accumulation, thereby stimulating cyclin dependent kinase 4 (CDK4) activity and G1 progression. However, we and others showed that accumulated cyclin D1 binds and inhibits AR activity, thereby engaging a negative feedback loop to attenuate subsequent mitogenic response in AR-positive PCa cells. These actions of cyclin D1 contribute to the observed cell cycle dependence of AR activity in PCa, wherein AR activity is inversely correlated with cyclin D1 expression. Thus, cyclin D1 serves as a "rheostat" that controls the strength and duration of the androgen response. The achieved goals of the first funding period were to dissect the mechanism and regulation of this cross-talk pathway in PCa. Our published and unpublished data demonstrate that cyclin D1 is a major effector of AR activity, and acts through defined mechanisms to alter both AR activity and androgen-dependent proliferation in PCa. Moreover, we demonstrated that aberrations in this process facilitate unleashed AR activity. Thus, this renewal application is based on the hypothesis that abrogation of cyclin D1 transcriptional regulatory function promotes unchecked AR activity in PCa cells, and provides a mechanism to promote tumor development and/or progression. The present renewal application will directly challenge this concept by dissecting the molecular impact of cyclin D1 action (and aberrations thereof) under conditions associated with tumor progression (aim 1), defining the consequence of cyclin D1b, a splice variant of cyclin D1 that is deficient in AR control and is induced in PCa, on androgen mediated gene regulation (aim 2), and determining the oncogenic capacity of cyclin D1b in the prostate (aim 3). PUBLIC HEALTH RELEVANCE: Fatal prostate cancer arises as a result of inappropriate androgen receptor (AR) activity, a protein that controls the action of testosterone. We discovered that aberrations in a second gene product (cyclin D1) serve to promote unchecked AR activity and tumor growth. Here, we will determine molecular mechanisms through which cyclin D1 controls AR and determine the importance of this protein in prostate cancer, with the long term goal of devising new therapies to treat this deadly disease.

描述（由申请人提供）：前列腺癌（PCa）细胞的生长和存活依赖于雄激素受体（AR）功能；这种依赖性被用于治疗播散性癌症，其中消除 AR 活性是治疗干预的第一线。虽然最初有效，但由于 AR 功能恢复不当，最终会出现复发性肿瘤。 AR 是 PCa 中 G1-S 相变的主要调节因子，对该机制的研究导致发现了 AR 和细胞周期途径之间的重要串扰机制。 Cyclin D1 是雄激素作用的主要效应器，在第一个资助期间描述的 PCa 中发挥专门功能。活性 AR 诱导细胞周期蛋白 D1 积累，从而刺激细胞周期蛋白依赖性激酶 4 (CDK4) 活性和 G1 进展。然而，我们和其他人表明，积累的细胞周期蛋白 D1 结合并抑制 AR 活性，从而参与负反馈循环，减弱 AR 阳性 PCa 细胞随后的有丝分裂反应。细胞周期蛋白 D1 的这些作用有助于观察到 PCa 中 AR 活性的细胞周期依赖性，其中 AR 活性与细胞周期蛋白 D1 表达呈负相关。因此，细胞周期蛋白 D1 充当“变阻器”，控制雄激素反应的强度和持续时间。第一个资助期实现的目标是剖析 PCa 中这种串扰路径的机制和调节。我们已发表和未发表的数据表明，细胞周期蛋白 D1 是 AR 活性的主要效应器，并通过确定的机制发挥作用，改变 PCa 中的 AR 活性和雄激素依赖性增殖。此外，我们证明了这个过程中的像差有助于释放 AR 活动。因此，这一更新申请基于这样的假设：细胞周期蛋白D1转录调节功能的废除会促进PCa细胞中不受控制的AR活性，并提供促进肿瘤发生和/或进展的机制。目前的更新申请将通过剖析与肿瘤进展相关的条件下细胞周期蛋白 D1 作用（及其畸变）的分子影响（目标 1）来直接挑战这一概念，定义细胞周期蛋白 D1b 的结果，细胞周期蛋白 D1b 是一种缺乏细胞周期蛋白 D1 的剪接变体在 AR 控制中，在 PCa 中诱导，在雄激素介导的基因调节上（目标 2），并确定前列腺中细胞周期蛋白 D1b 的致癌能力（目标3）。公共健康相关性：致命的前列腺癌是由于雄激素受体 (AR) 活性不当而引起的，雄激素受体 (AR) 是一种控制睾酮作用的蛋白质。我们发现第二种基因产物（细胞周期蛋白 D1）的畸变会促进不受控制的 AR 活性和肿瘤生长。在这里，我们将确定细胞周期蛋白 D1 控制 AR 的分子机制，并确定该蛋白在前列腺癌中的重要性，长期目标是设计新疗法来治疗这种致命疾病。