Differential regulation of E2F transcription factors by p53 tumor suppressor protein

The cell cycle is under the control of various positive and negative regula tors. Two such regulators are the E2F family of transcription factors and t he p53 tumor suppressor protein. While E2F proteins are implicated in promo ting the S phase of the cell cycle, p53 has the potential to arrest cells i n G(1) phase and thereby prevent entry into S phase. Because they perform s eemingly opposite functions in the control of cell growth, a possibility of functional interactions between E2F and p53 was investigated. It was found that p53 specifically inhibited activated transcription by E2F-5 but not b y E2F-1, Investigation into the mechanism of action established that hetero dimer formation and the DNA-binding steps were not significantly inhibited by p53, However, the transcriptional activation step of E2F-5 activity, as examined by using a Gal4 DNA-binding domain chimera, was specifically inhib ited by p53, Interestingly, p53 could also inhibit transcriptional activati on by E2F-4 but not by E2F-2 or E2F-3. The results indicate that p53 differ entially regulates the activities of two subclasses (E2F-1/-2/-3 vs. E2F-4/ -5) of E2F transcription factors. Detailed analysis using a two-hybrid appr oach in mammalian cells indicated lack of physical interaction between p53 and E2F-5, DP-1, or E2F-1. Reciprocal analysis revealed that whereas E2F-1 dramatically inhibited p53-activated transcription, E2F-5 or DP-1 did not. Thus, nonreciprocal functional interactions exist between various members o f the E2F family of transcription factors and p53 tumor suppressor protein. The complex interplay between various positive and negative regulators of cell growth, such as E2F and p53 proteins, may be crucial in determining th e ultimate outcome in terms of cell cycle arrest, cell growth, or apoptosis .