RI-alpha/RIAZ on Cell Growth in Breast Cancer

RI-α/RIAZ 对乳腺癌细胞生长的影响

• 批准号: 7422336
• 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
• 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/7422336
• 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

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得到深入研究，但其作用机制尚未完全了解。 cAMP的作用主要是由cAMP依赖性蛋白激酶（PKA）介导的，该蛋白激酶（PKA）由两个不同的亚基组成，分别是催化（C）和调节性（R），形成了四聚体全酶，R2C2。 I型调节性α（Rialpha）亚基表达与人类乳腺组织的过度增殖及其在人类乳腺癌中的过表达有关，与恶性肿瘤和预后不良有关。 RI表达增加？刺激生长，而C亚基的过表达不会产生这种后果。最近，Rialpha被证明是Carney Complex综合征中的肿瘤抑制基因。我们已经证明了与C亚基激酶活性无关的Rialpha的新型相互作用。在此应用中，我们通过酵母两杂交相互作用克隆实验显示了Rialpha与新型的BTB/POZ结构域锌指转录因子相关的，称为Rialpha相关的锌指蛋白（RIAZ）。我们证明了Riaz是一种cAMP响应转录激活因子，其与Rialpha的相互作用以及与CAMP反应元件结合蛋白（CREB）的相互作用调节。我们进一步表明，在大约15％的人类原发性乳腺癌中，Riaz异常表达。此外，RIAZ的过表达会导致[3H]胸苷摄取测量的生长抑制作用。 cAMP增强了生长抑制作用，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转导的生长抑制作用的新型转录机制。在此提案中，我们将：（1）确定RI的机制？与Riaz的相互作用和营地的监管； （2）研究RIAZ对CAMP的转录反应的机制； （3）研究RI的生长控制机制？与Riaz的互动以响应营地。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。