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: 8765280
• 负责人: HYESOOK KIM
• 金额: $ 99万
• 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 2015-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8765280
• 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; 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 酰化在细胞周期调节、细胞凋亡和信号转导中发挥着关键作用。 O-GlcNAc 转移酶对蛋白质的 O-GlcNAc 酰化修饰可通过 O-GlcNAcase 的活性来逆转。在丝氨酸或苏氨酸中添加和去除 O-GlcNAc 部分可直接或通过减少磷酸化来调节蛋白质的功能。 c-myc 蛋白的 O-GlcNAc 酰化可诱导泛素依赖性 c-myc 降解。 p53 的 GlcNAc 酰化可防止 p53 降解并稳定 p53 蛋白，这对癌细胞有益，因为它可以阻止细胞生长并诱导 DNA 损伤引起的细胞凋亡。为了阐明蛋白质 O-GlcNA 酰化的功能，有必要开发 O-GlcNA 酰化蛋白质的位点特异性抗体。迄今为止，很少有位点特异性抗体被成功生产。缺乏位点特异性 O-GlcNAcNA 酰化抗体会妨碍对该位点的轻松检测和定量，从而无法阐明 O-GlcNAc 酰化分子在生理学和疾病中的功能。 O-GlcNAcylation位点特异性抗体的出现将促进癌症中O-GlcNAcylation和磷酸化依赖性信号转导途径的机制研究，这将导致O-GlcNAcylation诱导抗癌药物的开发。