RI-α/RIAZ 对乳腺癌细胞生长的影响-猫眼课题宝

RI-α/RIAZ 对乳腺癌细胞生长的影响

批准号：

7628020

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

项目状态：

已结题

起止时间：

2005-08-10 至 2011-05-31

来源：

https://reporter.nih.gov/project-details/7628020

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 Cancer Cell Catalytic Domain Cell Cycle Cell Proliferation Chin Cloning Cyclic AMP Cyclic AMP-Responsive DNA-Binding Protein DNA Microarray Chip 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 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 breast tumorigenesis cell growth cell growth regulation insight malignant breast neoplasm novel outcome forecast overexpression programs protein complex protein expression protein kinase inhibitor research study response transcription factor uptake yeast two hybrid system

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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.

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