title: c-Myc-Induced Survivin Is Essential for Promoting  the Notch-Dependent T Cell Differentiation from  Hematopoietic Stem Cells.
abstract: Notch is indispensable for T cell lineage commitment, and is needed for thymocyte differentiation at early phases. During early stages of T cell development, active Notch prevents other lineage potentials including B cell lineage and myeloid cell (e.g., dendritic cell) lineage. Nevertheless, the precise intracellular signaling pathways by which Notch promotes T cell differentiation remain unclear. Here we report that the transcription factor c-Myc is a key mediator of the Notch signaling-regulated T cell differentiation. In a well-established in vitro differentiation model of T lymphocytes from hematopoietic stem cells, we showed that Notch1 and 4 directly promoted c-Myc expression; dominant-negative (DN) c-Myc inhibited early T cell differentiation. Moreover, the c-Myc expression activated by Notch signaling increased the expression of survivin, an inhibitor of apoptosis (IAP) protein. We further demonstrated that over-expression of c-Myc increased the abundance of survivin and the T cell differentiation thereof, whereas dn c-Myc reduced survivin levels and concomitantly retarded the differentiation. The c-Myc-dependent survivin induction is functionally germane, because Notch-dependent T cell differentiation was canceled by the depletion of survivin. These results identify both c-Myc and survivin as important mediators of the Notch signaling-regulated differentiation of T lymphocytes from hematopoietic stem cells.
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. songpsulab1@gmail.com.
authors.forename: Rizwanul
authors.initials: R
authors.lastname: Haque
authors.affiliation: Institutes of Irradiation/Immunology, The Third Military Medical University, Chongqing 400038, China. sdtohe@gmail.com.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. songpsulab2@gmail.com.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Haque
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. songpsulab1@yahoo.com.
authors.forename: Fengyang
authors.initials: F
authors.lastname: Lei
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. songpsulab2@yahoo.com.
authors.forename: Praneet
authors.initials: P
authors.lastname: Sandhu
authors.affiliation: Institutes of Irradiation/Immunology, The Third Military Medical University, Chongqing 400038, China. nibingtmmu@yahoo.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Ni
authors.affiliation: Department of Medicine, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. songpsulab3@yahoo.com.
authors.forename: Songguo
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. deyufangnwu@yahoo.com.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. songpsulab@gmail.com.
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. jus35@psu.edu.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Song
keywords: Notch signaling;  T cells;  cell differentiation;  c‐Myc;  hematopoietic stem cells