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

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(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