Parp Function in Prostate Cancer

Parp 在前列腺癌中的功能

• 批准号: 9285034
• 负责人: Bryce Paschal
• 金额: $ 37.05万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9285034
• 关键词: ADP Receptors; ADP Ribose Transferases; Address; American; Androgen Receptor; Androgens; Area; Arts; BRCA1 gene; BRCA2 gene; Binding Sites; Biochemical; Biological Assay; Biology; Castration; Catalytic Domain; Cause of Death; Cells; ChIP-seq; Clinical; Communication; Complex; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; Data; Enzymes; Family member; Gene Expression; Genetic Transcription; Genome; Genome Stability; Genomics; Genotype; Goals; Ionizing radiation; Ligands; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Mono(ADP-Ribose) Transferases; Mono-S; Multienzyme Complexes; Neoplasm Metastasis; PARP9 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphorylation; Poly Adenosine Diphosphate Ribose; Prostate; Prostate Cancer therapy; Proteins; Reaction; Recruitment Activity; Repair Complex; Resistance; Signal Transduction; Site; Therapeutic; Topoisomerase II; Work; androgen deprivation therapy; androgen sensitive; base; defined contribution; design; ds-DNA; experimental study; improved; improved outcome; inhibitor/antagonist; insight; killings; men; novel; personalized medicine; prostate cancer cell; prostate carcinogenesis; repaired; response; therapy resistant; transcription factor; tumor growth; tumorigenesis; ubiquitin ligase; ubiquitin-protein ligase

ABSTRACT The androgen receptor (AR) makes profound contributions to the biology of prostate cancer cells, principally through its function as a ligand-regulated transcription factor. As such, therapeutic approaches to prostate cancer are typically designed to deplete or compete with endogenous androgens with the goal of reducing the transcription function of AR. This proposal addresses a relatively unexplored area of AR action, which is how it generates and responds to DNA damage. In brief, we have developed a large set of preliminary data that shows AR is part of an signaling axis that is initiated by androgen, requires inputs from the DNA damage and repair machinery, and results in assembly of a DNA repair complex. We found that one of the key enzymes in this pathway is Parp7, a mono-ADP-ribosytransferase for which little is known. In Aim1 we will determine how Parp7 is regulated by androgen and DNA damage signaling in prostate cancer cells. In Aim2 we will determine how Parp7 regulates the assembly and DNA repair function of an E3 ubiquitin ligase/ADP-ribosyltransferase complex. In Aim3 we will define the contribution of the signaling axis to genome maintenance, tumorigenesis, and therapy response. The enzymes that mediate DNA damage response and repair reactions have emerged as actionable targets in malignancies including prostate cancer. Inhibitors to the poly-ADP-ribosyltransferase family member, Parp1, improve outcomes in therapy- resistant prostate cancer, though the benefit depends on the status of the DNA repair machinery, notably the BRCA1/BRCA2 genotype. Thus, while the clinical findings provide proof-of-principle for targeting DNA repair pathways, they also underscore the importance of defining and incorporating biochemical and genomic context into treatment rationale. In summary, our studies will define the biochemical relationships between androgen signaling and DNA damage and repair pathways, and help provide new insights into the vulnerabilities of prostate cancer cells.

摘要 雄激素受体（AR）对前列腺生物学做出了深远的贡献 癌细胞，主要是通过其作为配体调节的转录因子的功能。作为 这种前列腺癌的治疗方法通常被设计为消耗或 与内源性雄激素竞争以降低转录功能 的AR。该提案涉及AR行动的一个相对未探索的领域，即如何 产生并应对DNA损伤。简而言之，我们已发展了一套 初步数据显示AR是由雄激素启动的信号轴的一部分， 需要DNA损伤和修复机制的输入，并导致 DNA修复复合体。我们发现，在这一途径中的关键酶之一是Parp 7， 一种单ADP核糖基转移酶，对此知之甚少。在目标1中，我们将确定如何 在前列腺癌细胞中，Parp 7受雄激素和DNA损伤信号的调节。在 目的2我们将确定Parp 7是如何调节细胞的组装和DNA修复功能的。 E3泛素连接酶/ADP-核糖基转移酶复合物。在Aim 3中，我们将定义 信号传导轴对基因组维持、肿瘤发生和治疗的贡献 反应介导DNA损伤反应和修复反应的酶有 在包括前列腺癌在内的恶性肿瘤中成为可操作的靶点。抑制剂 聚ADP核糖基转移酶家族成员Parp 1改善治疗结果- 抵抗性前列腺癌，尽管益处取决于DNA修复的状态， BRCA 1/BRCA 2基因型。因此，虽然临床结果 为靶向DNA修复途径提供了原理证明，他们还强调了 定义和纳入生物化学和基因组背景的重要性 治疗原理。总之，我们的研究将确定生物化学关系 雄激素信号传导与DNA损伤和修复途径之间的联系， 对前列腺癌细胞脆弱性的新见解。