A Transcriptionally Inactive E2F-1 Targets the MDM Family of Proteins for Proteolytic Degradation

E2F-1-activated transcription promotes cell cycle progression and apoptosis. These functions are regulated by several factors including the E2F-1-binding protein MDM2 and the retinoblastoma protein pRb. Using a yeast two-hybrid screen we have identified the MDM2-related protein, MDMX, as an E2F-1-bi...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-12, Vol.276 (49), p.45677-45685
Main Authors: Strachan, Gordon D., Rallapalli, Ravikumar, Pucci, Bruna, Lafond, Toulouse P., Hall, David J.
Format: Article
Language:English
Subjects:
Base Sequence
Cell Cycle Proteins
Cell Line
Cysteine Endopeptidases - metabolism
DNA Primers
DNA-Binding Proteins
E2F Transcription Factors
E2F1 protein
E2F1 Transcription Factor
Humans
Hydrolysis
MDM2 protein
MDMX protein
Multienzyme Complexes - metabolism
Mutagenesis, Site-Directed
Nuclear Proteins
Proteasome Endopeptidase Complex
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-mdm2
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
Two-Hybrid System Techniques
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Summary:E2F-1-activated transcription promotes cell cycle progression and apoptosis. These functions are regulated by several factors including the E2F-1-binding protein MDM2 and the retinoblastoma protein pRb. Using a yeast two-hybrid screen we have identified the MDM2-related protein, MDMX, as an E2F-1-binding protein. In these studies we find that coexpression of MDMX with E2F-1 results in degradation of the MDMX protein. Although this proteolytic degradation can be blocked by the protease inhibitors bafilomycin A1, N-acetyl-Leu-Leu-Norleu-AL, and N-acetyl-Leu-Leu-Met-AL, MDMX degradation is not inhibited by lactacystin, suggesting that degradation occurs by a proteasome-independent mechanism. Using an E2F-1 deletion mutant (E2F-1(180–437)) we show that E2F-1-targeted degradation of MDMX does not require the E2F-1 DNA binding domain and therefore is independent of E2F-1-driven transcription. We also find that this transcriptionally inactive E2F-1 mutant is capable of degrading the MDMX-related protein MDM2 and the MDMX isoform MDMX-S. Mapping of the E2F-1 C terminus reveals that neither a previously characterized C-terminal MDM2 binding domain nor the pRb binding domain on E2F-1 is required for MDMX and MDM2 degradation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M103765200