Faculty Collaboration Database

Aberrant regulation of survivin by the RB/E2F family of proteins. J Biol Chem 2004 Sep 24;279(39):40511-20

Date

07/24/2004

Pubmed ID

15271987

DOI

10.1074/jbc.M404496200

Scopus ID

2-s2.0-4644348204 (requires institutional sign-in at Scopus site)   153 Citations

Abstract

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.

Author List

Jiang Y, Saavedra HI, Holloway MP, Leone G, Altura RA

Author

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenoviridae
Animals
Blotting, Northern
Blotting, Western
Cell Cycle
Cell Cycle Proteins
Cell Line
Cells, Cultured
Chromatin
DNA Damage
DNA-Binding Proteins
Disease Progression
E2F Transcription Factors
E2F1 Transcription Factor
E2F2 Transcription Factor
E2F3 Transcription Factor
Fibroblasts
Gene Deletion
Gene Expression Regulation
Genes, Reporter
Humans
Inhibitor of Apoptosis Proteins
Mice
Microtubule-Associated Proteins
Mutation
Neoplasm Proteins
Plasmids
Precipitin Tests
Promoter Regions, Genetic
Protein Binding
Retinoblastoma Protein
Retroviridae
Reverse Transcriptase Polymerase Chain Reaction
Time Factors
Transcription Factors
Transcription, Genetic
Transfection