title: DNA double-strand break - induced pro-survival signaling.
abstract: Radiation and other types of DNA damaging agents induce a plethora of signaling events simultaneously originating from the nucleus, cytoplasm, and plasma membrane. As a result, this presents a dilemma when seeking to determine causal relationships and better insight into the intricacies of stress signaling. ATM plays critical roles in both nuclear and cytoplasmic signaling, of which, the DNA damage response (DDR) is the best characterized. We have recently created experimental conditions where the DNA damage signal alone can be studied while minimizing the influence from the extranuclear compartment. We have been able to document pro-survival and growth promoting signaling (via ATM-AKT-ERK) resulting from low levels of DSBs (equivalent to ≤2 Gy). More extensive DSBs (>2 Gy eq.) result in phosphatase-mediated ERK dephosphorylation, and thus shutdown of ERK signaling. In contrast, radiation does not result in such dephosphorylation even at very high doses. We propose that phosphatases are inactivated perhaps as a result of reactive oxygen species, which does not occur in response to 'pure' DNA damage. Our findings suggest that clinically relevant radiation doses, which are intended to halt tumor growth and induce cell death, are unable to inhibit tumor pro-survival signaling via ERK dephosphorylation.
authors: Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA 23298-0058, USA.
authors: Amy J
authors: AJ
authors: Hawkins
authors: Sarah E
authors: SE
authors: Golding
authors: Ashraf
authors: A
authors: Khalil
authors: Kristoffer
authors: K
authors: Valerie
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D004260:DNA Repair / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology / Q000528:radiation effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000528:radiation effects; D015398:Signal Transduction / Q000235:genetics* / Q000528:radiation effects*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000528:radiation effects
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt