title: Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-Myc and other stem cell transcription factors.
abstract: Signaling through the thrombospondin-1 receptor CD47 broadly limits cell and tissue survival of stress, but the molecular mechanisms are incompletely understood. We now show that loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division, and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. c-Myc, Klf4, Oct4, and Sox2 expression is elevated in CD47-null endothelial cells, in several tissues of CD47- and thrombospondin-1-null mice, and in a human T cell line lacking CD47. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells and in vivo, whereas CD47 ligation by thrombospondin-1 suppresses c-Myc expression. The inhibitory effects of increasing CD47 levels can be overcome by maintaining c-Myc expression and are absent in cells with dysregulated c-Myc. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute.
authors.forename: Sukhbir
authors.initials: S
authors.lastname: Kaur
authors.forename: David R
authors.initials: DR
authors.lastname: Soto-Pantoja
authors.forename: Erica V
authors.initials: EV
authors.lastname: Stein
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pendrak
authors.forename: Alina
authors.initials: A
authors.lastname: Nicolae
authors.forename: Satya P
authors.initials: SP
authors.lastname: Singh
authors.forename: Zuqin
authors.initials: Z
authors.lastname: Nie
authors.forename: David
authors.initials: D
authors.lastname: Levens
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Isenberg
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D000818:Animals; D051928:CD47 Antigen / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D019700:Thrombospondin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051928:CD47 Antigen; C497895:Cd47 protein, mouse; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D019700:Thrombospondin 1; D014157:Transcription Factors