title: Low dose IR-induced IGF-1-sCLU expression: a p53-repressed expression cascade that interferes with TGFβ1 signaling to confer a pro-survival bystander effect.
abstract: Inadvertent mammalian tissue exposures to low doses of ionizing radiation (IR) after radiation accidents, remediation of radioactive-contaminated areas, space travel or a dirty bomb represent an interesting trauma to an organism. Possible low-dose IR-induced bystander effects could impact our evaluation of human health effects, as cells within tissue are not equally damaged after doses of IR ≤10 cGy. To understand tissue responses after low IR doses, we generated a reporter system using the human clusterin promoter fused to firefly luciferase (hCLUp-Luc). Secretory clusterin (sCLU), an extracellular molecular chaperone, induced by low doses of cytotoxic agents, clears cell debris. Low-dose IR (≥2 cGy) exposure induced hCLUp-Luc activity with peak levels at 96 h, consistent with endogenous sCLU levels. As doses increased (≥1 Gy), sCLU induction amplitudes increased and time-to-peak response decreased. sCLU expression was stimulated by insulin-like growth factor-1, but suppressed by p53. Responses in transgenic hCLUp-Luc reporter mice after low IR doses showed that specific tissues (that is, colon, spleen, mammary, thymus and bone marrow) of female mice induced hCLUp-Luc activity more than male mice after whole body (≥10 cGy) irradiation. Tissue-specific, non-linear dose- and time-responses of hCLUp-Luc and endogenous sCLU levels were noted. Colon maintained homeostatic balance after 10 cGy. Bone marrow responded with delayed, but prolonged and elevated expression. Intraperitoneal administration of α-transforming growth factor (TGF)β1 (1D11), but not control (13C4) antibodies, immediately following IR exposure abrogated CLU induction responses. Induction in vivo also correlated with Smad signaling by activated TGFβ1 after IR. Mechanistically, media with elevated sCLU levels suppressed signaling, blocked apoptosis and increased survival of TGFβ1-exposed tumor or normal cells. Thus, sCLU is a pro-survival bystander factor that abrogates TGFβ1 signaling and most likely promotes wound healing.
authors.affiliation: Radiological Protection Research and Instrumentation Branch, Chalk River Laboratories, Atomic Energy Canada Limited, Chalk River, ON, USA.
authors.forename: D
authors.initials: D
authors.lastname: Klokov
authors.forename: K
authors.initials: K
authors.lastname: Leskov
authors.forename: S
authors.initials: S
authors.lastname: Araki
authors.forename: Y
authors.initials: Y
authors.lastname: Zou
authors.forename: E M
authors.initials: EM
authors.lastname: Goetz
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.forename: D
authors.initials: D
authors.lastname: Willson
authors.forename: D A
authors.initials: DA
authors.lastname: Boothman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001853:Bone Marrow / Q000378:metabolism / Q000528:radiation effects; D045744:Cell Line, Tumor; D051152:Clusterin / Q000235:genetics* / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000528:radiation effects; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D005260:Female; D005720:Gamma Rays; D045325:HCT116 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000528:radiation effects; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014916:Whole-Body Irradiation
chemical_list: D051152:Clusterin; D018832:Molecular Chaperones; D051785:Smad Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I