Critical Functions for Notch Dimerization In T Cell Transformation.

Abstract 3647

Notch1 encodes an essential transmembrane receptor that is frequently mutated in T-ALL. Notch signaling regulates cell fate decisions, proliferation, survival and metabolism by activating transcription; yet the mechanism by which Notch selectively activates different transcriptional targets is poorly understood. After ligand-induced proteolysis, the intracellular part of Notch (ICN) generates signals by entering the nucleus and forming a transcriptional activation complex with the transcription factor CSL and the co-activator Mastermind (MAML). This complex can bind DNA as a monomer [1-3], however it can also dimerize on sites in which a pair of head-to-head CSL binding sites is properly spaced (so-called paired sites) [4, 5]. Whether Notch dimerization is physiologically important is unknown. Using T cell development and transformation as models, we now report that dimeric Notch transcriptional complexes are required for leukemic transformation but dispensable for T cell fate specification from a multipotential precursor. The varying requirements for Notch dimerization within the T cell lineage result from the differential sensitivity of specific Notch target genes. One particularly important dimerization-dependent target of Notch, required for both T cell maturation and leukemogenesis, is the proto-oncogene c-Myc, whereas other well-characterized target genes, such as Hey1, show no dimerization-dependence. These findings identify functionally important differences in the responsiveness among Notch target genes attributable to the formation of higher-order complexes. Our data suggest that it may be possible to develop a new class of Notch inhibitors, which selectively block outcomes that are dependent on Notch dimerization (e.g., leukemogenesis).

References:

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