Kaiso磷酸化的功能及其与胃癌发生的关系

Kaiso(ZBTB33), which binds to DNA sequence and p120-catenin, regulates the transcription of MMP7, cyclin D1, MTA2 and other genes to inhibit tumor cells’ proliferation and invasion by binding to methylated DNA sequence CGCG and conserved binding sequence TCCTGCNA （Kaiso binding sequences, KBS). In our previous work, we found that the binding of Kaiso to DNA sequences was related to its phosphorylation. Phosphorylated Kaiso translocated into cytoplasm and lost its binding ability with DNA. Based on this, we want to ascertain the phosphorylation sites of Kaiso through Mass Spectra and make sure that whether the phosphorylation impacts its binding to p120-catenin. We will prepare the antibody specifically to phosphorylated Kaiso to explore the role of its phosphorylation in carcinogenesis and progression in gastric cancer. We also want to explore the kinases or phosphotases, which regulate Kaiso phosphorylation in tumors’ proliferation and invasion. These works will give a more comprehensive understanding of the phosphorylation of Kaiso in malignant transformation.

已知转录调节因子Kaiso（ZBTB33)既可以和DNA也可以和p120-catenin结合。其DNA结合序列包括甲基化的CGCG和非甲基化的TCCTGCNA，调节MMP7、cyclin D1、MTA2等基因的转录,抑制肿瘤细胞的增殖和侵袭。我们前期研究发现，Kaiso与DNA的结合能力受其磷酸化状态的影响：只有未磷酸化者能够结合靶DNA，磷酸化后的Kaiso将转运到胞浆。本项目拟在上述工作基础上，对下列问题开展研究：①用磷酸化质谱鉴定Kaiso的磷酸化位点；②研究Kaiso磷酸化对其与p120-catenin结合能力的影响；③制备磷酸化Kaiso特异性抗体，分析Kaiso磷酸化在胃癌发生发展过程中的变化规律；④探索影响这些位点磷酸化的磷酸激酶或磷酸酶。这些研究对进一步明确Kaiso磷酸化发生的机制及其功能有重要意义。