E2F1 Destruction Pathway
E2F-1 is a transcription factor that regulates the expression of genes involved in the cell cycle and that is involved in progression of the cell cycle from G1 into S phase. Over-expression of E2F-1 can induce cellular transformation and its under-expression can repress apoptosis. Association with the tumor suppressor Rb represses E2F-1 activity, and this repression is relieved when the cdk2/cyclin E complex at the G1 to S phase transition phosphorylates Rb. Like many cell cycle regulators, E2F-1 is regulated through phosphorylation by a cyclin-dependent protein kinase, cdk2/cyclin A, and by proteolytic degradation. Phosphorylation of E2F-1 by cdk2/cyclin A leads to E2F-1 inactivation, blocking DNA binding. E2F-1 is also regulated through degradation in the proteosome at the S/G2 transition. The F box complex that degrades E2F-1 contains components shared with the complexes that target other cell cycle factors for degradation. The F box protein that specifically recruits E2F for ubiquitination and degradation is Skp2. Other components of the SCF complex include Skp1, Cul1, and cdc34. Skp2 expression is cyclical, increasing in the S/G2 transition as E2F-1 is degraded. Knowledge of E2F-1 activity and its regulation form part of the complex set of interactions regulating the cell cycle and potential targets for the treatment of cancer.
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REFERENCES: J. Wade Harper and Stephen J. Elledge (1999) Skipping into the E2F1-destruction pathway. Nature Cell Bio. Vol 1: May 1999:E5-7 Marti, A, et al. (1999) Interaction between ubiquitin-protein ligase SCF skp2 and E2F-1 underlies the regulation of E2F-1 degradation. Nature Cell Bio, Vol 1: May 1999: 14-19
