ヘリコバクター・ピロリ菌感染を起点とする胃癌発症機構の解析

(1)幽门螺杆菌CagA与胃癌的发生。幽门螺杆菌毒力因子CagA通过Src家族激酶进行酪氨酸磷酸化。我们发现，酪氨酸磷酸化的CagA蛋白特异性结合SHP-2或Csk和失调的催化活性。CagA激活的SHP-2引起持续激活Erk MAP激酶，从而诱导细胞形态转化，提高细胞运动性以及异常细胞生长。SHP-2与CagA的含有EPIYA的区域结合，这表明西方和东亚CagA物种之间存在显着的序列差异。结果表明，东亚CagA物种比西方CagA物种表现出更强的SHP-2结合活性和更大的病理活性。(2)pRB家族肿瘤抑制蛋白的功能和调节：我们发现pRB家族蛋白（pRB，p107和p130）的细胞周期抑制活性由细胞周期蛋白E a共同调节。 ...更多信息 和细胞周期蛋白D依赖性磷酸化。我们还发现，p107在S期细胞响应DNA损伤的生长停滞中起着重要作用。此外，我们发现，pRB家族蛋白能够转录诱导细胞周期蛋白D1，无论其磷酸化状态。(3)ESXR 1的分子克隆与分析我们分离到一个新的人类基因ESXR 1，它编码一个配对样同源异型蛋白ESXR 1。在细胞中，ESXR 1被蛋白水解加工成N-末端含有同源结构域的片段和C-末端片段。C-末端片段定位于细胞质，并通过抑制M期细胞周期蛋白的降解诱导M期阻滞。另一方面，N端片段定位于细胞核，并作为转录抑制因子。通过基因芯片的全基因组筛选，我们确定K-ras基因为ESXR 1的靶基因之一。ESXR 1 N-末端片段的异位表达特异性抑制了K-ras基因中携带功能获得性突变的人类癌细胞的生长。少

(1) Helicobacter pylori CagA and gastric carcinogenesisUpon translocation into host gastric epithelial cells, H. pylori virulence factor CagA undergoes tyrosine phosphorylation by Src family kinases. We found that the tyrosine-phosphorylated CagA protein specifically binds to SHP-2 or Csk and deregulates the catalytic activity. CagA-activated SHP-2 elicited sustained-activation of Erk MAP kinase and thereby induced cell-morphological transformation, elevated cell motility as well as abnormal cell growth. SHP-2 binds to the EPIYA-containing region of CagA, which shows a significant sequence difference between Western and East Asian CagA species. As a result, East Asian CagA species exhibited stronger SHP-2 binding activity and greater pathological activity than Western CagA species.(2) Function and regulation of the pRB family tumor suppressor proteins.We found that the cell cycle-inhibitory activity of the pRB family proteins (pRB, p107 and p130) is collectively regulated by cyclin E a … More nd cyclin D-dependent phosphorylation. We also found that p107 plays a major role in the growth arrest of cells in S-phase in response to DNA damage. Furthermore, we found that pRB family proteins are capable of transcriptionally inducing cyclin D1 regardless of their phosphorylation status.(3) Molecular cloning and analysis of ESXR1We isolated a new human gene, ESXR1, which encodes a paired-like homeoprotein ESXR1. In cells, ESXR1 is proteolytically processed into an N-terminal homeo domain-containing fragment and a C-terminal fragment. The C-terminal fragment localized to the cytoplasm and induced M-phase arrest by inhibiting degradation of M-phase cyclins. On the other hand, the N-terminal fragment localized to the nucleus and acted as a transcriptional repressor. Through genome-wide screening using DNA microarray, we identified the K-ras gene as one of the ESXR1 target genes. Ectopic expression of the ESXR1 N-terminal fragment specifically inhibited growth of human cancer cells that carry gain-of-function mutations in the K-ras gene. Less