SBIR PHASE II: SITE-SPECIFIC ANTIBODIES FOR GLCNACYLATED PROTEINS IN CANCER

SBIR 第二阶段：针对癌症中的糖基化蛋白的位点特异性抗体

• 批准号: 9915346
• 负责人: HYESOOK KIM
• 金额: $ 1.03万
• 依托单位: DETROIT R & D, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2016-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915346
• 关键词: Antibodies; Antibody Formation; Antigens; Antineoplastic Agents; Apoptosis; Breast Cancer Cell; Cell Cycle Regulation; Cells; DNA Damage; Detection; Development; Disease; Estrogen Receptor alpha; Excision; Human; Malignant Neoplasms; Modification; Mus; Normal Cell; O-GlcNAc transferase; Peptide antibodies; Peptides; Phase; Phosphorylation; Physiology; Play; Production; Protein p53; Proteins; Proto-Oncogene Proteins c-myc; Role; Serine; Signal Transduction; Signal Transduction Pathway; Site; Small Business Innovation Research Grant; TP53 gene; Threonine; Ubiquitin; c-myc Genes; cancer cell; cell growth; inhibitor/antagonist; monoclonal antibody production; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; polyclonal antibody; prevent; protein function; response

O-GlcNAcylation of proteins plays a critical role in cell cycle regulation, apoptosis and signal transduction. Modification of O-GlcNAcylation of proteins by O-GlcNAc transferase is reversible by the activity of O-GlcNAcase. Addition and removal of O-GlcNAc moiety to serine or threonine regulate the function of proteins directly or via decreased phosphorylation. O-GlcNAcylation of c-myc proteins induces ubiquitin-dependent c-myc degradation. GlcNAcylation of p53 prevents p53 degradation and stabilizes p53 proteins, which are beneficial in cancer cells by arresting cell growth and inducing apoptosis in response to DNA damage. To elucidate functions of O-GlcNAcylation of the proteins it is necessary to develop site-specific antibodies for O-GlcNAcylated proteins. Few site-specific antibodies have been successfully produced so far. A lack of site-specific O-GlcNAcylated Abs prevents facile detection and quantitation of the site to elucidate the function of O-GlcNAcylated molecules in physiology and disease. Availability of O-GlcNAcylation site-specific antibodies will facilitate mechanistic studies on O-GlcNAcylation ¿ and phosphorylation-dependent signal transduction pathway in cancer, which will result in development of O-GlcNAcylation-inducing anti-cancer drugs.

蛋白质的O-GlcNAc化在细胞周期调控、细胞凋亡和信号转导中起关键作用。O-GlcNAc转移酶对蛋白质的O-GlcNAc化的修饰通过O-GlcNAc酶的活性是可逆的。在丝氨酸或苏氨酸上添加和去除O-GlcNAc部分直接或通过降低磷酸化来调节蛋白质的功能。c-myc蛋白的O-GlcNAc化诱导泛素依赖性c-myc降解。p53的GlcNAc酰化防止p53降解并稳定p53蛋白，这通过响应于DNA损伤而阻止细胞生长和诱导细胞凋亡而在癌细胞中是有益的。为了阐明蛋白质的O-GlcNAc酰化的功能，有必要开发针对O-GlcNAc酰化蛋白质的位点特异性抗体。到目前为止，很少有位点特异性抗体被成功地生产出来。缺乏位点特异性O-GlcNAc酰化抗体阻碍了对该位点的简单检测和定量，从而无法阐明O-GlcNAc酰化分子在生理学和疾病中的功能。O-GlcNAc酰化位点特异性抗体的获得将促进对癌症中O-GlcNAc酰化和磷酸化依赖性信号转导途径的机制研究，这将导致开发O-GlcNAc酰化诱导的抗癌药物。