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Cyclin E-induced S phase without activation of the pRb/E2F pathway
J Lukas1, T Herzinger, K Hansen
1Danish Cancer Society, Division of Cancer Biology, Copenhagen.
Genes & Development
|June 1, 1997
Summary
Cyclin E, not cyclin D1, can overcome cell cycle arrest by promoting S-phase entry. This cyclin E-driven cell cycle progression occurs independently of E2F transcription factors, suggesting an alternative pathway for cell division.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cyclin-dependent kinases (CDKs) regulate the cell cycle, particularly the G1 to S-phase transition.
- Phosphorylation of the retinoblastoma protein (pRb) by CDKs releases E2F transcription factors, activating S-phase genes.
Purpose of the Study:
- To investigate the role of G1 cyclins (D1 and E) in cell cycle progression.
- To explore the relationship between cyclin E, E2F, and S-phase induction.
- To elucidate the mechanisms by which cyclin E promotes cell division.
Main Methods:
- Microinjection and transfection experiments in rat R12 fibroblasts and human U-2-OS cells.
- Overexpression of cyclins D1 or E, p16INK4a inhibitor, and dominant-negative DP-1 mutant.
- Quantitative reporter assays to assess E2F activation in live cells.
Main Results:
- Ectopic expression of cyclin E, but not cyclin D1, overrides G1 arrest induced by p16INK4a or a phosphorylation-deficient pRb mutant.
- Cyclin E promotes S-phase entry and cell cycle completion independently of E2F-mediated transactivation.
- Cyclin E overcomes G1 arrest caused by dominant-negative DP-1, indicating an E2F-independent mechanism.
Conclusions:
- A novel cyclin E-controlled event promotes S-phase entry in somatic cells, acting downstream or parallel to pRb phosphorylation and independent of E2F.
- Hyperactivation of this cyclin E-controlled pathway can compensate for the lack of E2F-mediated transactivation.
- These findings reveal an alternative mechanism for cell cycle control by cyclin E in higher eukaryotes.