NOTCH INHIBITION OF E47 SUPPORTS THE EXISTENCE OF A NOVEL SIGNALING PATHWAY

E47 is a widely expressed transcription factor that activates B-cell-s pecific immunoglobulin gene transcription and is required for early B- cell development. In an effort to identify processes that regulate E47 , and potentially B-cell development, we found that activated Notch1 a nd Notch2 effectively inhibit E47 activity. Only the intact E47 protei n was inhibited by Notch-fusion proteins containing isolated DNA bindi ng and activation domains were unaffected-suggesting that Notch target s an atypical E47 cofactor, although overexpression of the coactivator p300 partially reversed E47 inhibition, results of several assays ind icated that p300/CBP is not a general target of Notch, Notch inhibitio n of E47 did not correlate with its ability to activate CBF1/RBP-J kap pa, the mammalian homolog of Suppressor of Hairless, a protein that as sociates physically with Notch and defines the only known Notch signal ing pathway in drosophila. Importantly, E47 was inhibited independentl y of CBF1/RPB-J kappa by Deltex, a second Notch-interacting protein. W e provide evidence that Notch and Deltex may act on E47 by inhibiting signaling through Ras because (i) full E47 activity was found to be de pendent on Ras and (ii) both Notch and Deltex inhibited GAL4-Jun, a hy brid transcription factor whose activity is dependent on signaling fro m Ras to SAPK/JNK.