RI-alpha/RIAZ on Cell Growth in Breast Cancer

RI-α/RIAZ 对乳腺癌细胞生长的影响

基本信息

批准号：
7233691
负责人：
KHEW-VOON CHIN
金额：
$ 21.16万
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：
2005
资助国家：
美国
起止时间：
2005-08-10 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7233691
关键词：
A kinase anchoring protein AT-Hook Motifs Abbreviations Acute Promyelocytic Leukemia Affect Apoptosis Atrial myxoma with lentigines B-Cell Lymphomas BCL6 gene BTB/POZ Domain Binding Binding Proteins Breast Breast Cancer Cell Catalytic Domain Cell Cycle Cell Proliferation Chin Cloning Complex Cyclic AMP Cyclic AMP-Responsive DNA-Binding Protein DNA Microarray Chip DNA Microarray format Fingers Genes Genetic Transcription Glutathione Glutathione S-Transferase Green Fluorescent Proteins Growth Holoenzymes Human Light Malignant Neoplasms Mammary Gland Parenchyma Measures Mediating Molecular Neoplastic Cell Transformation Phosphotransferases Poxviridae Protein Kinase Protein Kinase Inhibitors Protein Overexpression Proteins RNA Interference Regulation Research Personnel Response Elements Signal Transduction Small Interfering RNA Syndrome Testing Thymidine Transcription Coactivator Transcriptional Regulation Tumor Suppressor Genes Yeasts ZNF145 gene Zinc Zinc Fingers base cell growth cell growth regulation insight malignant breast neoplasm novel outcome forecast programs protein expression protein kinase inhibitor research study response transcription factor tumorigenesis uptake yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The effects of cAMP on cell growth and proliferation have been intensely investigated, but its mechanisms of action are not completely understood. The effects of cAMP are predominantly mediated by the cAMP-dependent protein kinase (PKA), which is composed of two distinct subunits, catalytic (C) and regulatory (R), forming a tetrameric holoenzymes, R2C2. The type I regulatory alpha (RIalpha) subunit expression is associated with hyperproliferation in human breast tissue and its overexpression in human breast cancer correlates with malignancy and poor prognosis. Increased expression of RI? stimulates growth, whereas overexpression of the C subunit does not produce such consequence. Most recently, RIalpha was shown to be a tumor suppressor gene in Carney Complex Syndrome. We have demonstrated previously novel interaction of RIalpha that is independent of the C subunit kinase activity. In this application, we show by yeast two-hybrid interaction cloning experiment that RIalpha associates with a novel BTB/POZ domain zinc finger transcription factor, termed RIalpha-associated zinc finger protein (RIAZ). We demonstrate that RIAZ is a cAMP-responsive transcriptional activator regulated by its interaction with RIalpha and potential cooperation with the cAMP-response element binding protein (CREB). We show further that RIAZ is aberrantly expressed in approximately 15% of human primary breast cancer. Furthermore, overexpression of RIAZ causes growth inhibition measured by [3H]thymidine uptake. The growth inhibition is enhanced by cAMP but not affected by the PKA inhibitor H-89. We hypothesize that RI? interaction with RIAZ may be a novel transcriptional mechanism in growth inhibition transduced by cAMP. In this proposal, we will: (1) determine the mechanisms of RI? interaction with RIAZ and regulation by cAMP; (2) investigate the mechanisms of RIAZ transcriptional response to cAMP; and (3) investigate the mechanisms of growth control by RI? interaction with RIAZ in response to cAMP. Our results will shed light on this novel interaction of RIalpha with RIAZ in growth inhibition.

描述（由申请人提供）：cAMP 对细胞生长和增殖的影响已被深入研究，但其作用机制尚未完全了解。 cAMP 的作用主要由 cAMP 依赖性蛋白激酶 (PKA) 介导，PKA 由两个不同的亚基组成：催化 (C) 和调节 (R)，形成四聚体全酶 R2C2。 I 型调节 α (RIalpha) 亚基表达与人类乳腺组织的过度增殖相关，其在人类乳腺癌中的过度表达与恶性肿瘤和不良预后相关。 RI 表达增加？刺激生长，而 C 亚基的过度表达不会产生这样的结果。最近，RIalpha 被证明是卡尼复合综合征中的肿瘤抑制基因。我们之前已经证明了 RIalpha 的新颖相互作用，其独立于 C 亚基激酶活性。在本申请中，我们通过酵母双杂交相互作用克隆实验表明，RIalpha 与一种新型 BTB/POZ 结构域锌指转录因子相关，称为 RIalpha 相关锌指蛋白 (RIAZ)。我们证明 RIAZ 是一种 cAMP 响应性转录激活剂，通过与 RIalpha 的相互作用以及与 cAMP 响应元件结合蛋白 (CREB) 的潜在合作来调节。我们进一步表明，RIAZ 在大约 15% 的人类原发性乳腺癌中异常表达。此外，RIAZ 的过度表达会导致通过[3H]胸苷摄取测量的生长抑制。 cAMP 可增强生长抑制作用，但不受 PKA 抑制剂 H-89 的影响。我们假设 RI？与 RIAZ 的相互作用可能是 cAMP 转导的生长抑制中的一种新的转录机制。在这个提案中，我们将：（1）确定RI的机制？与 RIAZ 的相互作用以及 cAMP 的调节； (2)研究RIAZ对cAMP转录反应的机制； (3) 研究 RI 控制生长的机制？与 RIAZ 相互作用以响应 cAMP。我们的结果将揭示 RIalpha 与 RIAZ 在生长抑制中的这种新型相互作用。