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Abstract
The Notch signaling pathway appears to perform an important function in a wide variety of organisms and cell types. In our present study, we provide evidence that UV irradiation-induced Tip60 proteins reduced Notch1 activity to a marked degree. Accumulated UV irradiation-induced Tip60 suppresses Notch1 transcriptional activity via the dissociation of the Notch1-IC-CSL complex. The binding between endogenous Tip60 and Notch1-IC in UV radiation-exposed cells was verified in this study by coimmunoprecipitation. Interestingly, the physical interaction of Tip60 with Notch1-IC occurs to a more profound degree in the presence of CSL but does not exist in a trimeric complex. Using Notch1-IC and Tip60 deletion mutants, we also determined that the N terminus, which harbors the RAM domain and seven ankyrin repeats of Notch1-IC, interacts with the zinc finger and acetyl coenzyme A domains of Tip60. Furthermore, here we report that Notch1-IC is a direct target of the acetyltransferase activity of Tip60. Collectively, our data suggest that Tip60 is an inhibitor of the Notch1 signaling pathway and that Tip60-dependent acetylation of Notch1-IC may be relevant to the mechanism by which Tip60 suppresses Notch1 signaling.
We thank Thomas Südhof (University of Texas Southwestern), S.-H. Baek (Seoul National University), and Saadi Khochbin (INSERM) for providing the Tip60 constructs; Raphael Kopan (Washington University School of Medicine) for the Notch-related constructs; and K.-W. Kim (Seoul National University) for the anti-acetyl-Lys antibody.
This research was supported by a Korea Research Foundation grant (KRF-2004-C00141) funded by the Korean government (MOEHRD, Basic Research Promotion Fund) (to H.-S.P.).