Regulation of cyclin E protein levels through E2F-mediated inhibition of degradation.
Cyclin E is a key cell cycle regulator, whose accumulation is believed to be positively modulated chiefly at the transcriptional level. We show that forced expression of E2F family members specifically stabilizes cyclin E protein by reducing its conjugation with ubiquitin, leading to increased steady-state levels. The stabilized protein shows enhanced association with cdk2 and higher kinase activity, indicating that cyclin E stabilization bears functional consequences. Although the activity of E2F on the cyclin E protein does not entail increased cyclin E gene transcription, it does require the E2F transactivation capacity, as demonstrated by E2F and DP-1 mutant analysis. However, such activity does not require E2F binding to pRb. Furthermore, E2F stabilizes cyclin E even in nonproliferating cells. Our results bear significance for the understanding of tumor progression, in light of the well-known autoregulatory loop between E2F and cyclin E and the disregulation of E2F that is one consequence of the almost universal impairment of the pRb pathway in cancer. Constitutive pRb inactivation leads to enhanced E2F activity through loss of binding. We propose that such increased E2F activity stabilizes cyclin E and contributes to establish the high and persistent levels of the protein commonly found in human neoplasias.
Pajalunga
Deborah
D
Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Roma, Italy.
Crescenzi
Marco
M
D000818:Animals; D002467:Cell Nucleus; D002478:Cells, Cultured; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D015870:Gene Expression; D051379:Mice; D009154:Mutation / Q000235:genetics; D032446:Myoblasts; D041681:NIH 3T3 Cells; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection
D019927:Cyclin E; D050684:E2F Transcription Factors; D012333:RNA, Messenger