The Notch Intracellular Domain Can Function as a Coactivator for LEF-1

Abstract

Notch signaling commences with two ligand-mediated proteolysis events that release the Notch intracellular domain, NICD, from the plasma membrane. NICD then translocates into the nucleus and interacts with the DNA binding protein CSL to activate transcription. We found that NICD expression also potentiates activity of the transcription factor LEF-1. NICD stimulation of LEF-1 activity was context dependent and occurred on a subset of promoters distinct from those activated by β-catenin. Importantly, the effect of NICD does not appear to be mediated through canonical components of the Wnt signaling pathway or downstream components of the Notch pathway. In vitro assays show a weak association between the C-terminal transactivation domain of NICD and the high-mobility group domain of LEF-1, suggesting that the two proteins interact in vivo. Our data therefore describe a new nuclear target of Notch signaling and a new coactivator for LEF-1.

ACKNOWLEDGMENTS

We thank members of the Kadesch lab for their helpful comments and suggestions.

This work was supported by a grant from the National Institutes of Health to T.K. (RO1 GM58228); D.R. was supported by a National Institutes of Health National Cancer Institute training grant (T32 CA09140).