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E2F integrates and coordinates cell cycle progression with the transcription apparatus through its cyclical interactions with important regulators of cellular proliferation, such as pRb, cyclins, and cdk's. Physiological E2F is a heterodimeric transcription factor composed of an E2F and a DP family member, and while E2F proteins can stimulate proliferation, certain members of the family are known to be endowed with growth-inhibitory and tumor suppressor-like activity. We have investigated the product of the human mdm2 oncogene, hDM2, and report on its ability to regulate E2F-dependent apoptosis in a fashion that is independent of p53. hDM2 can prevent p53(-/-) cells from entering E2F-dependent apoptosis, an outcome that is dependent upon the presence of the DP subunit. Cells rescued from apoptosis possess lower levels of E2F subunits, although the rescued cells show an increase in DNA synthesis and possess enhanced viability that reflects cooperation between E2F-DP and hMD2. Furthermore, the regulation of E2F activity correlates with an hDM2-dependent effect on the intracellular distribution of DP-1, since hDM2 causes the nuclear accumulation of DP-1. The control of E2F by hDM2 therefore has certain parallels with the targeted degradation by MDM2 of p53. However, the domains in hDM2 required for the regulation of E2F activity can be distinguished from those necessary for p53 degradation, suggesting that control of E2F and p53 by hDM2 may be mechanistically distinct. These experiments define a new level of interplay between E2F and hDM2 whereby hDM2 has a profound impact on the physiological consequences of E2F activation. They suggest that the oncogenic properties of hDM2 may in part be mediated by an antiapoptotic activity that converts E2F from a negative to a positive regulator of cell cycle progression and thereby retains E2F at a level that contributes to a continual state of growth stimulation.

Type

Journal article

Journal

Mol Cell Biol

Publication Date

03/2000

Volume

20

Pages

2186 - 2197

Keywords

Animals, Apoptosis, Carrier Proteins, Cell Cycle, Cell Cycle Proteins, Cell Line, DNA-Binding Proteins, E2F Transcription Factors, Fibroblasts, Gene Expression Regulation, Humans, Mice, Nuclear Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Retinoblastoma-Binding Protein 1, Transcription Factor DP1, Transcription Factors, Tumor Suppressor Protein p53