title: Regulation of lymphocyte development by cell-type-specific interpretation of Notch signals.
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 mitogen-activated protein kinase (MAPK)-dependent degradation of E2A transcription factors and Janus kinases, molecules essential for both B- and T-lymphocyte development. However, these events occur in B lymphocytes, 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 the expression of Notch-resistant E2A and constitutively active STAT5 in mice neutralized the 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.
authors.affiliation: Program in Immunobiology and Cancer Research, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Nie
authors.forename: S Scott
authors.initials: SS
authors.lastname: Perry
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jiaxue
authors.initials: J
authors.lastname: Huang
authors.forename: Paul W
authors.initials: PW
authors.lastname: Kincade
authors.forename: Michael A
authors.initials: MA
authors.lastname: Farrar
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Sun
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins; D002460:Cell Line; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D053612:Janus Kinases / Q000378:metabolism; D038041:Lymphopoiesis / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011828:Radiation Chimera; D051881:Receptor, Notch1 / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D053612:Janus Kinases; D008565:Membrane Proteins; D046988:Proteasome Endopeptidase Complex; D051881:Receptor, Notch1; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D025801:Ubiquitin; C512941:DLK1 protein, human; C497762:Notch1 protein, mouse; C075668:Tcf3 protein, mouse