title: The influence of p53 functions on radiation-induced inflammatory bystander-type signaling in murine bone marrow.
abstract: Radiation-induced bystander and abscopal effects, in which DNA damage is produced by inter-cellular communication, indicate mechanisms of generating damage in addition to those observed in directly irradiated cells. In this article, we show that the bone marrow of irradiated p53(+/+) mice, but not p53(-/-) mice, produces the inflammatory pro-apoptotic cytokines FasL and TNF-α able to induce p53-independent apoptosis in vitro in nonirradiated p53(-/-) bone marrow cells. Using a congenic sex-mismatch bone marrow transplantation protocol to generate chimeric mice, p53(-/-) hemopoietic cells functioning in a p53(+/+) bone marrow stromal microenvironment exhibited greater cell killing after irradiation than p53(-/-) hemopoietic cells in a p53(-/-) microenvironment. Cytogenetic analysis demonstrated fewer damaged p53(-/-) cells in a p53(+/+) microenvironment than p53(-/-) cells in a p53(-/-) microenvironment. Using the two different model systems, the findings implicate inflammatory tissue processes induced as a consequence of p53-dependent cellular responses to the initial radiation damage, producing cytokines that subsequently induce ongoing p53-independent apoptosis. As inactivation of the p53 tumor suppressor pathway is a common event in malignant cells developing in a stromal microenvironment that has normal p53 function, the signaling processes identified in the current investigations have potential implications for disease pathogenesis and therapy.
authors.affiliation: University of Dundee, Centre for Oncology and Molecular Medicine, Division of Medical Science, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Lorimore
authors.forename: Shubhra
authors.initials: S
authors.lastname: Rastogi
authors.forename: Debayan
authors.initials: D
authors.lastname: Mukherjee
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Coates
authors.forename: Eric G
authors.initials: EG
authors.lastname: Wright
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001853:Bone Marrow / Q000473:pathology / Q000528:radiation effects*; D024201:Bystander Effect / Q000528:radiation effects*; D060833:Cellular Microenvironment; D005260:Female; D007249:Inflammation / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53