The retinoblastoma gene product protects E2F-1 from degradation by the ubiquitin-proteasome pathway.
E2F-1 plays a crucial role in the regulation of cell-cycle progression at the G1-S transition. In keeping with the fact that, when overproduced, it is both an oncoprotein and a potent inducer of apoptosis, its transcriptional activity is subject to multiple controls. Among them are binding by the retinoblastoma gene product (pRb), activation by cdk3, and S-phase-dependent down-regulation of DNA-binding capacity by cyclin A-dependent kinase. Here we report that E2F-1 is actively degraded by the ubiquitin-proteasome pathway. Efficient degradation depends on the availability of selected E2F-1 sequences. Unphosphorylated pRb stabilized E2F-1, protecting it from in vivo degradation. pRb-mediated stabilization was not an indirect consequence of G1 arrest, but rather depended on the ability of pRb to interact physically with E2F-1. Thus, in addition to binding E2F-1 and transforming it into a transcriptional repressor, pRb has another function, protection of E2F-1 from efficient degradation during a period when pRb/E2F complex formation is essential to regulating the cell cycle. In addition, there may be a specific mechanism for limiting free E2F-1 levels, failure of which could compromise cell survival and/or homeostasis.
Hofmann
F
F
The Division of Neoplastic Disease Mechanisms, Dana-Farber Cancer Institute, The Harvard Medical School, Boston, Massachusetts 02115, USA.
Martelli
F
F
Livingston
D M
DM
Wang
Z
Z
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005822:Genetic Vectors; D006207:Half-Life; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex; D016160:Retinoblastoma Protein / Q000378:metabolism*; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; 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; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D014452:Ubiquitins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex