Growth factor-dependent regulation of survivin by c-myc in human breast cancer.
Survivin has emerged as a unique regulator of cell death through its response to growth factors, such as basic fibroblast growth factor (bFGF), which we have previously shown to be mitogen-activated protein kinase (MAPK) dependent. The transcriptional complex myc/max is an oncogene that lies downstream of the MAPK pathway, suggesting a possible role in survivin's regulation. In this study, we investigated the ability of bFGF to induce signalling of the MAPK effector transcription factor c-myc in human breast cancer. Treatment of SK-BR-3 breast cancer cell line with growth factor induced survivin expression and recruitment of c-myc to its response element in the promoter region of the target gene survivin as demonstrated by electromobility shift analysis and chromatin immunoprecipitation assays. The promoter region of survivin was assessed using bioinformatic techniques and DNA footprinting. Overexpression of c-myc increased survivin protein expression. This effect was eliminated when siRNA against c-myc was transfected into the cells. c-Myc drove transcriptional activity of survivin when transfected into SK-BR-3 cells with a luciferase reporter vector harbouring the c-myc response element specific for survivin. Using confocal fluorescent microscopy, myc was located to the nucleus of breast tumour epithelial cells and was found to be significantly associated with survivin (P < 0.0001). These data provide evidence that growth factors can signal through the transcription factor c-myc in human breast cancer. They also indicate a role for c-myc in the transcriptional regulation of survivin in breast cancer.
Cosgrave
Niamh
N
School of Medicine and Medical Sciences, UCD Conway Institute of Biomolecular and Biomedical Research, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Hill
Arnold D K
AD
Young
Leonie S
LS
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D000077022:Survivin; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D000077022:Survivin; D016222:Fibroblast Growth Factor 2