Abstract
The E2F family of transcription factors plays an essential role in promoting cell cycle progression, and one member of the family, E2F-1, is also capable of inducing apoptosis. We show here that E2F-1 can induce apoptosis by a death receptor-dependent mechanism, by downregulating TRAF2 protein levels and inhibiting activation of antiapoptotic signals including NF-kappa B. In this way, E2F-1 expression can lead to the sensitization of cells to apoptosis by a number of agents independently of p53. Deregulation of E2F-1 activity occurs in the majority of human tumors, and the ability of E2F-1 to inhibit antiapoptotic signaling may contribute to the enhanced sensitivity of transformed cells to chemotherapeutic agents.
Publication types
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- Animals
- Apoptosis* / drug effects
- Carrier Proteins*
- Caspase Inhibitors
- Caspases / metabolism
- Cell Cycle Proteins*
- Cell Line
- DNA / biosynthesis
- DNA-Binding Proteins*
- Down-Regulation
- E2F Transcription Factors
- E2F1 Transcription Factor
- Gene Expression
- Humans
- I-kappa B Kinase
- JNK Mitogen-Activated Protein Kinases
- Mice
- Mitogen-Activated Protein Kinases / antagonists & inhibitors
- Mitogen-Activated Protein Kinases / metabolism
- Mutation / genetics
- NF-kappa B / antagonists & inhibitors
- NF-kappa B / chemistry
- NF-kappa B / genetics
- NF-kappa B / metabolism
- Protein Serine-Threonine Kinases / antagonists & inhibitors
- Protein Serine-Threonine Kinases / metabolism
- Proteins / genetics
- Proteins / metabolism
- Receptors, Tumor Necrosis Factor / drug effects
- Receptors, Tumor Necrosis Factor / metabolism
- Retinoblastoma Protein / genetics
- Retinoblastoma Protein / metabolism
- Retinoblastoma-Binding Protein 1
- S Phase
- Signal Transduction* / drug effects
- TNF Receptor-Associated Factor 2
- Transcription Factor DP1
- Transcription Factors / chemistry
- Transcription Factors / genetics
- Transcription Factors / metabolism*
- Tumor Necrosis Factor-alpha / pharmacology
- Tumor Suppressor Protein p53 / genetics
- Tumor Suppressor Protein p53 / physiology
Substances
- Arid4a protein, mouse
- Carrier Proteins
- Caspase Inhibitors
- Cell Cycle Proteins
- DNA-Binding Proteins
- E2F Transcription Factors
- E2F1 Transcription Factor
- E2F1 protein, human
- E2f1 protein, mouse
- NF-kappa B
- Proteins
- Receptors, Tumor Necrosis Factor
- Retinoblastoma Protein
- Retinoblastoma-Binding Protein 1
- TNF Receptor-Associated Factor 2
- Transcription Factor DP1
- Transcription Factors
- Tumor Necrosis Factor-alpha
- Tumor Suppressor Protein p53
- DNA
- Protein Serine-Threonine Kinases
- CHUK protein, human
- Chuk protein, mouse
- I-kappa B Kinase
- IKBKB protein, human
- IKBKE protein, human
- Ikbkb protein, mouse
- Ikbke protein, mouse
- JNK Mitogen-Activated Protein Kinases
- Mitogen-Activated Protein Kinases
- Caspases