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Mol. Cell. Biol. doi:10.1128/MCB.00844-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Regulation of lymphocyte development by cell type-specific interpretation of Notch signals

Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104; Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455

^* To whom correspondence should be addressed. Email: sunx{at}omrf.ouhsc.edu.

	Abstract

Notch signaling pathways exert diverse biological effects depending on the cellular context where Notch receptors are activated. How Notch signaling is integrated with environmental cues is a central issue. Here, we show that Notch activation accelerates ubiquitin-mediated and MAP kinase (MAPK)-dependent degradation of E2A transcription factors and Janus kinases (Jak), molecules essential for both B and T lymphocyte development. However, these events occur in B but not T lymphocytes due to their different levels of MAPK, thus providing one mechanism whereby Notch inhibits B cell development without impairing T cell differentiation. Lymphoid progenitors expressing a Notch-resistant E2A mutant differentiated into B lineage cells on stromal cells expressing Notch ligands and in the thymus of transplant recipients. Bone marrow transplant assays and examination of steady-state B lymphopoiesis also revealed that expression of Notch-resistant E2A and constitutively active STAT5 in mice neutralized effects of Notch-induced degradation, allowing B cell development through a bone marrow-like program in the thymus. These findings illustrate that Notch function can be influenced by MAPKs, producing distinct outcomes in different cellular contexts.