Regulation of E2F through ubiquitin-proteasome-dependent degradation: stabilization by the pRB tumor suppressor protein.
The E2F family of transcription factors plays a key role in regulating cell-cycle progression. Accordingly, E2F is itself tightly controlled by a series of transcriptional and posttranscriptional events. Here we provide evidence that E2FI protein levels are regulated by the ubiquitin-proteasome-dependent degradation pathway. An analysis of E2F1 mutants identified a conserved carboxyl-terminal region, which is required for eliciting ubiquitination and protein turnover. Fusion of this E2F1 carboxyl-terminal sequence to a heterologous protein, GAL4, resulted in destabilization of GAL4. Previous studies identified an overlapping region of E2F1 that facilitates complex formation with retinoblastoma tumor suppressor protein, pRB, and we found that pRB blocks ubiquitination and stabilizes E2F1. These results suggest a new mechanism for controlling the cell-cycle regulatory activity of E2F1.
Campanero
M R
MR
Division of Tumor Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Flemington
E K
EK
D000818:Animals; D002352:Carrier Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002846:Chromatography, Affinity; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D007700:Kinetics; D009097:Multienzyme Complexes / Q000378:metabolism*; D012516:Osteosarcoma; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D056465:Retinoblastoma-Binding Protein 1; D017384:Sequence Deletion; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000378:metabolism*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009097:Multienzyme Complexes; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D014452:Ubiquitins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex