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

✍ Scribed by Alexandre Chlenski; Kathleen V. Ketels; J. Luke Engeriser; Mark S. Talamonti; Ming-Sound Tsao; Hanna Koutnikova; Ryoichi Oyasu; Dante G. Scarpelli

• Book ID: 101235558
• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: French
• Weight: 374 KB
• Volume: 83
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19991029)83:3<349::aid-ijc10>3.0.co;2-c

✦ Synopsis

We 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-2Јdeoxycytidine 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.