ネズミニオケル2-アセトアミドフルオレン - インドールシュヨウハッセイニオヨボスカンゾウドク（シエンカタンソオヨビｄｌ－エチオニン）マエショチノコウカニツイテ

京都大学0048新制・論文博士医学博士乙第230号論医博第109号新制||医||50(附属図書館)549UT51-51-L149(主査)教授 岡本 耕造, 教授 荒木 千里, 教授 西村 秀雄学位規則第5条第2項該当Kyoto UniversityDA

zo-2 gene alternative promoters in normal and neoplastic human pancreatic duct cells

International audienceWe have observed that 2 forms of zonula occludens 2 (ZO-2) protein, ZO-2A and ZO-2C, are expressed in normal human pancreatic duct cells, but only ZO-2C in pancreatic duct adenocarcinoma. We report here partial organization of the zo-2 gene. Transcription of 2 forms of ZO-2 mRNA is driven by alternative promoters P(A) and P(C). Lack of expression of ZO-2A in neoplastic cells is caused by inactivation of the downstream promoter P(A). Analysis of the promoter P(A) sequence and function in normal and neoplastic cells demonstrated that neither structural changes (mutations) nor a change in the pool of transcription factors is responsible for its inactivation. Although hypermethylation was found in a large number of cancer clones, treatment with 5-aza-2'-deoxycytidine did not fully cause the promoter function to recover. We conclude that the initial down-regulation of zo-2 promoter P(A) activity in pancreatic duct carcinomas is due to the structural or functional alteration(s) in the regulatory elements, localized outside the analyzed promoter region. Methylation of P(A) is responsible for the inactivation of the suppressed promoter at the late stages of tumor development