Mxi1 is a potential cellular target of carcinogens and frequently mutated in experimental rat tumors and tumor cell lines.

Abstract

Mxi1, a member of the Myc family of transcription factors, negatively regulates Myc oncoprotein activity and thus may be a tumor suppressor gene. It is mutated in a few human prostate cancers. Rat Mxi1 was isolated as a selective overexpressive message in rat esophageal cancer induced by N-nitrososarcosine ethyl ester using differential display and polymerase chain reaction cloning. Reverse transcription, single-strand conformation polymorphism analysis and subsequent DNA sequencing were used to screen mutations for the rat Mxi1 coding region including the functional domains, Sin3-interacting, helix-loop-helix and leucine zipper in samples from 24 rat tumor tissues and various cell lines. Seven mutations were revealed to exist in six rat tumors (including two esophageal tumors and a breast cancer), and three rat tumor cell lines: Leydig cell tumor, osteogenic sarcoma, and pituitary tumor. No coding changes were detected in 34 samples of human sporadic gastric adenocarcinoma. A silent base substitution (GAG to GAA) at codon 131 was also identified in six rat tumors as well as in one human gastric cancer. Our results indicate that Mxi1 is often mutated in experimental rat tumors but mutations are rare in human sporadic cancers. The Mxi1 tumor suppressor gene may be a cellular target of strong carcinogens. Considering the frequency of mutations in chemical carcinogen-induced tumors, searches for Mxi1 mutation in human tumors should be directed toward patients with a specific epidemiological background.