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

蛋白质的O-GlcN酰化在细胞周期调节、细胞凋亡和信号转导中起着关键作用。O-GlcNAc转移酶对蛋白质的O-GlcN酰化修饰是通过O-GlcNAcase的活性可逆的。丝氨酸或苏氨酸上的O-GlcNAc部分的添加和去除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-GlcN酰化可诱导泛素依赖的c-myc降解。P53的GlcN酰化可以阻止P53的降解并稳定P53蛋白，这些蛋白通过抑制细胞生长和诱导细胞凋亡来应对DNA损伤，从而对癌细胞有利。为了阐明O-GlcN酰化蛋白的功能，有必要研制针对O-GlcN酰化蛋白的位点特异性抗体。到目前为止，几乎没有成功地生产出部位特异性抗体。O-GlcNacylated Abbs的缺乏阻碍了对O-GlcNacylated Abbs位点的检测和定量，从而无法阐明O-GlcNacylated分子在生理和疾病中的功能。O-GlcN酰化位点特异性抗体的问世将有助于肿瘤中O-GlcN酰化和磷酸化依赖的信号转导途径的机制研究，这将导致O-GlcN酰化诱导抗癌药物的开发。

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.