Structure-expression relationships of the 15-kDa selenoprotein gene - Possible role of the protein in cancer etiology

Selenium has been implicated in cancer prevention, but the mechanism and po ssible involvement of seleno-proteins in this process are not understood. T o elucidate whether the 15-kDa selenoprotein may play a role in cancer etio logy, the complete sequence of the human 15-kDa protein gene was determined , and various characteristics associated with expression of the protein wer e examined in normal and malignant cells and tissues. The 51-kilobase pair gene for the 15-kDa selenoprotein consisted of five exons and four introns and was localized on chromosome 1p31, a genetic locus commonly mutated or d eleted in human cancers. Two stem-loop structures resembling selenocysteine insertion sequence elements were identified in the 3'-untranslated region of the gene, and only one of these was functional. Two alleles in the human 15-kDa protein gene were identified that differed by two single nucleotide polymorphic sites that occurred within the selenocysteine insertion sequen ce-like structures. These S'-untranslated region polymorphisms resulted in changes in selenocysteine incorporation into protein and responded differen tly to selenium supplementation. Human and mouse 15-kDa selenoprotein genes manifested the highest level of expression in prostate, liver, kidney, tes tis, and brain, and the level of the selenoprotein was reduced substantiall y in a malignant prostate cell line and in hepatocarcinoma. The expression pattern of the 15-kDa protein in normal and malignant tissues, the occurren ce of polymorphisms associated with protein expression, the role of seleniu m in differential regulation of polymorphisms, and the chromosomal location of the gene may be relevant to a role of this protein in cancer.