Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo

M. Mancuso, E. Pasquali, S. Leonardi, S. Rebessi, M. Tanori, P. Giardullo, F. Borra, S. Pazzaglia, C.C. Naus, V. Di Majo, A. Saran

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Abstract

Ionizing radiation is a genotoxic agent and human carcinogen. Recent work has questioned long-held dogmas by showing that cancer-associated genetic alterations occur in cells and tissues not directly exposed to radiation, questioning the robustness of the current system of radiation risk assessment. In vitro, diverse mechanisms involving secreted soluble factors, gap junction intercellular communication (GJIC) and oxidative metabolism are proposed to mediate these indirect effects. In vivo, the mechanisms behind long-range bystander responses remain largely unknown. Here, we investigate the role of GJIC in propagating radiation stress signals in vivo, and in mediating radiation-associated bystander tumorigenesis in mouse central nervous system using a mouse model in which intercellular communication is downregulated by targeted deletion of the connexin43 (Cx43) gene. We show that GJIC is critical for transmission of oncogenic radiation damage to the non-targeted cerebellum, and that a mechanism involving adenosine triphosphate release and upregulation of Cx43, the major GJIC constituent, regulates transduction of oncogenic damage to unirradiated tissues in vivo. Our data provide a novel hypothesis for transduction of distant bystander effects and suggest that the highly branched nervous system, similar to the vascular network, has an important role. © 2011 Macmillan Publishers Limited All rights reserved.
Original languageEnglish
Pages (from-to)4601 - 4608
Number of pages8
JournalOncogene
Volume30
Issue number45
DOIs
Publication statusPublished - 10 Nov 2011
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Mancuso, M., Pasquali, E., Leonardi, S., Rebessi, S., Tanori, M., Giardullo, P., Borra, F., Pazzaglia, S., Naus, C. C., Di Majo, V., & Saran, A. (2011). Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo. Oncogene, 30(45), 4601 - 4608. https://doi.org/10.1038/onc.2011.176