Aberrant regulation of survivin by the RB/E2F family of proteins.
Survivin is a putative oncogene that is aberrantly expressed in cancer cells. It has been hypothesized to play a central role in cancer progression and resistance to therapy in diverse tumor types. Although some of the transcriptional processes regulating its expression have been established, the diversity of genes that may be controlling the levels of its expression in both normal cells as well as in cancer cells has not been fully explored. The most common genetically mutated pathways in human malignancies are the p53 tumor suppressor pathway and the RB/E2F pathway. Both of these pathways, when intact, provide essential checkpoints in the maintenance of normal cell growth and protect the cell from DNA damage. Using non-transformed embryonic fibroblasts, we provide evidence of a molecular link between the regulation of survivin transcription and the RB/E2F family of proteins. We demonstrate that both pRB and p130 can interact with the survivin promoter and can repress survivin transcription. We also show that the E2F activators (E2F1, E2F2, and E2F3) can bind to the survivin promoter and induce survivin transcription. Genetically modified cells that harbor deletions in various members of the RB/E2F family confirm our data from the wild-type cells. Our findings implicate several members of the RB/E2F pathway in an intricate mechanism of survivin gene regulation that, when genetically altered during the process of tumorigenesis, may function within cancer cells to aberrantly alter survivin levels and enhance tumor progression.
Columbus Children's Research Institute, College of Medicine and Public Health, Ohio State University, 43210, USA.
Yuying
Y
Jiang
Harold I
HI
Saavedra
Michael P
MP
Holloway
Gustavo
G
Leone
Rachel A
RA
Altura
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D018450:Disease Progression; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
C107489:BIRC5 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D050699:E2F3 Transcription Factor; C493754:E2f1 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein; D000077022:Survivin; D014157:Transcription Factors