A mutation found in the promoter region of the human survivin gene is correlated to overexpression of survivin in cancer cells.
Survivin, a unique antiapoptotic factor, plays an important role in cell cycle regulation. Numerous clinical studies have shown that survivin is markedly overexpressed in most common types of cancer, suggesting that transcriptional deregulation is a major mechanism involved in aberrant expression of survivin in cancers. In this study, we have identified several polymorphisms in the survivin gene promoter. One of these polymorphisms is located at CDE/CHR repressor elements, and appears to be a common mutation with high frequency among cancer cell lines compared to normal cell line controls. The presence of the mutation was correlated in these cell lines with increased survivin expression at the both mRNA and protein levels. Furthermore, gel mobility shift analysis and transcriptional analysis showed the mutation changed cell cycle-dependent transcription by modifying the binding motif of the CDE/CHR repressor. These results indicate that the high level of survivin in some cancers is, at least in part, due to a genetic defect in the promoter region of the human survivin gene, which causes derepression of survivin transcription apparently due to the mutated CDE/CHR repressor binding motifs.
Xu
Yong
Y
Section of Molecular and Cellular Biology, Department of Biological Sciences, University of Kentucky, Lexington 40536-0305, USA. yxu0@pop.uky.edu
Fang
Fang
F
Ludewig
Gabriele
G
Jones
Grace
G
Jones
Davy
D
D001483:Base Sequence; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D014162:Transfection; D014407:Tumor Cells, Cultured
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin