REGULATION OF E2F4 MITOGENIC ACTIVITY DURING TERMINAL DIFFERENTIATIONBY ITS HETERODIMERIZATION PARTNERS FOR NUCLEAR TRANSLOCATION

E2F/DP heterodimers play a pivotal role in the regulation of cell grow th and differentiation, A decrease in E2F/DP activity occurs during ce ll cycle arrest and differentiation, However, very Little is known abo ut the specific role of the various E2F/DP members along the transitio n from proliferation to terminal differentiation. We have previously s hown that E2F4 accounts for the vast majority of the endogenous E2F in differentiating muscle cells, Here, we show that E2F4, which lacks a nuclear localization signal (nls), is distributed in both the nucleus and the cytoplasm, in either asynchronously growing myoblasts or diffe rentiated myotubes, E2F4 nuclear accumulation is induced by the bindin g in the cytoplasm with specific partners p107, pRb2/p130, and DP3 del ta, an nls-containing spliced form of DP3, which provide the nls, Alth ough overexpression of E2F4/DP3 delta reactivates the cell cycle in qu iescent cells, the E2F4 nuclear accumulation induced by pRb2/p130 and p107 correlates with cell growth arrest, Moreover, E2P4/DP3 delta-indu ced cell cycle reactivation is efficiently counteracted by either p107 or pRb2/p130 overexpression. Reinduction in quiescent cells of DNA sy nthesis by E2F1/DP1 overexpression is abrogated by coexpression of pRb and is hampered by MyoD overexpression. Both pRb2/p130 and pRb, as we ll as MyoD, are up-regulated in myotubes, Accordingly, multinucleated myotubes, which are induced to reenter the S-phase by oncoviral protei ns, are refractory to cell cycle reactivation by forced expression of E2F4/DP3 delta or E2F1/DP1. Thus, E2F/DP repression represents only on e of multiple redundant circuits that control the postmitotic state in terminally differentiated cells and that are targeted by adenovirus E 1A and SV40 large T antigen.