Synergistic Inhibitors of CREB-mediated Gene Transcription

CREB介导的基因转录的协同抑制剂

• 批准号: 10464627
• 负责人: Xiangshu Xiao
• 金额: $ 32.01万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464627
• 关键词: Antineoplastic Agents; Attenuated; Binding; Binding Proteins; Cancer Patient; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Responsive DNA-Binding Protein; EP300 gene; Exhibits; Genetic Transcription; Goals; Growth Factor; Malignant Neoplasms; Mediating; Mitogen-Activated Protein Kinases; Normal Cell; Normal tissue morphology; Nuclear; Organ; PTEN gene; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Prognosis; Protein Kinase; Protein phosphatase; Proto-Oncogene Proteins c-akt; Regulation; Research; Ribosomal Protein S6 Kinase; Signal Transduction; Somatotropin; Therapeutic; Tumor Tissue; cancer cell; extracellular; in vitro activity; in vivo; inhibitor; inorganic phosphate; insight; malignant breast neoplasm; novel; overexpression; paralogous gene; preclinical study; promoter; recruit; small molecule inhibitor; transcription factor

Public Abstract The goal of this application is to develop synergistic inhibitors of CREB-mediated gene transcription. Cyclic-AMP-response element binding protein (CREB) is a 43 kD nuclear transcription factor. Its transcription activity is critically dependent on phosphorylation on Ser133 to be induced by extracellular signals including growth factors and hormones. CREB is overexpressed and/or overactivated in tumor tissues of different organs compared to normal tissue. CREB's transcription activity is activated upon phosphorylation at Ser133 by a variety of protein kinases including protein kinase A (PKA), mitogen-activated protein kinases (MAPKs), protein kinase B (PKB/Akt) and protein ribosomal S6 kinase (pp90RSK). Once phosphorylated, CREB can bind with CREB-binding protein (CBP) and its paralog p300 to recruit other components in the transcriptional machinery to the CREB promoter to initiate CREB-dependent gene transcription. CREB's phosphorylation in normal cells is tightly regulated and very dynamic. Until now, three protein phosphatases have been identified to be able to remove the phosphate from CREB to attenuate its transcription activity. They are protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A) and phosphatase and tensin homolog (PTEN). Mechanistically, the kinases are often overactivated in cancer cells while the phosphatases are often inactivated in cancer cells. As a consequence, CREB is often overactivated in cancer cells compared to normal cells. Higher expression and/or activation of CREB is associated with poorer prognosis in cancer patients. Preclinical studies have validated CREB as an appealing target for various cancers. We recently identified various chemotypes as small molecule inhibitors of CREB or potentiators to exhibit synergistic activity in inhibiting CREB-mediated gene transcription. In this application, we will further develop these inhibitors and potentiators as synergistic inhibitors of CREB-mediated gene transcription. We will further study their mechanism of action and synergistic anti-breast cancer activity in vitro and in vivo. Accomplishing the proposed studies will provide novel insights into the mechanism of CREB regulation and provide potential cancer therapeutics.

公共摘要 本应用的目标是开发CREB介导的基因的协同抑制剂 抄写。环磷酸腺苷反应元件结合蛋白(CREB)是一个43kD的核蛋白 转录因子。其转录活性在很大程度上依赖于磷酸化 Ser133由细胞外信号诱导，包括生长因子和激素。 CREB在不同器官肿瘤组织中的过度表达和/或过度激活 与正常组织相比。CREB的转录活性被激活 包括蛋白激酶A在内的多种蛋白激酶对Ser133的磷酸化作用 (PKA)、丝裂原活化蛋白激酶(MAPKs)、蛋白激酶B(PKB/Akt)和 蛋白核糖体S6激酶(Pp90RSK)。一旦被磷酸化，CREB就可以与 CREB结合蛋白(CBP)及其Paralog p300在细胞内募集其他成分 CREB启动子启动CREB依赖基因的转录机制 抄写。CREB在正常细胞中的磷酸化受到严格调控，并且非常 活力四射。到目前为止，已经鉴定出三种蛋白磷酸酶能够 从CREB中去除磷酸盐以减弱其转录活性。它们是蛋白质 磷酸酶1(PP1)、蛋白磷酸酶2A(PP2A)与磷酸酶和紧张素 同源基因(PTEN)。从机制上讲，癌细胞中的激酶经常被过度激活。 而癌细胞中的磷酸酶通常是失活的。因此，CREB 与正常细胞相比，癌细胞中的这种基因经常被过度激活。更高的表达和/或 CREB的激活与癌症患者预后较差有关。临床前 研究证实CREB是治疗各种癌症的一个有吸引力的靶点。我们最近 鉴定了各种化学类型作为CREB的小分子抑制物或增强剂 在抑制CREB介导的基因转录方面表现出协同活性。在这 应用，我们将进一步开发这些缓蚀剂和增效剂作为增效剂 CREB介导的基因转录的抑制物。我们将进一步研究它们的作用机制。 体内外抗乳腺癌作用及协同作用。完成以下任务 拟议的研究将为CREB的调节和机制提供新的见解 提供潜在的癌症治疗方法。