Regulation of tumor suppressor gene FUS1 expression by the untranslated regions of mRNA in human lung cancer cells.

FUS1, also known as tumor suppressor candidate 2 (TUSC2), is a tumor suppressor gene located in the human chromosome 3p21.3 region. FUS1 mRNA transcripts could be detected on Northern blots in both normal lung and some lung cancer cell lines, but no endogenous FUS1 protein could be detected in a majority of lung cancer cell lines and small cell and non-small cell lung tumor tissues. However, mechanisms regulating FUS1 protein expression and its inactivation in primary lung cancer cells are largely unknown. In this study, we investigated the role of the 5'- and 3'-untranslated regions (UTRs) of the FUS1 gene transcript in the regulation of FUS1 protein expression. We identified RNA sequence elements in FUS1 UTRs that regulate FUS1 protein expression. We found that two small upstream open-reading frames in the 5'UTR of FUS1 mRNA could inhibit the translational initiation of FUS1 protein by interfering with the "scanning" of the ribosome initiation complexes. Several secondary RNA structural elements/motifs on the 3'UTR of FUS1 also exhibited a significant inhibitory effect on FUS1 protein expression. The 3'UTR-mediated regulatory effect on FUS1 protein expression was also differentially detected in normal lung epithelial and fibroblast cells compared with lung cancer cells. Our results provide new insight into the molecular mechanisms involved in the regulation of FUS1 expression.