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zo‐2 gene alternative promoters in normal and neoplastic human pancreatic duct cells
Author(s) -
Chlenski Alexandre,
Ketels Kathleen V.,
Engeriser J. Luke,
Talamonti Mark S.,
Tsao MingSound,
Koutnikova Hanna,
Oyasu Ryoichi,
Scarpelli Dante G.
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19991029)83:3<349::aid-ijc10>3.0.co;2-c
Subject(s) - promoter , transcription (linguistics) , biology , pancreatic cancer , gene , cancer research , transcription factor , methylation , dna methylation , microbiology and biotechnology , gene expression , cancer , genetics , linguistics , philosophy
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‐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. Int. J. Cancer 83:349–358, 1999. © 1999 Wiley‐Liss, Inc.