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

D. Klokov, K. Leskov, S. Araki, Y. Zou, E. M. Goetz, X. Luo, D. Willson, D. A. Boothman

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)479-490
Number of pages12
JournalOncogene
Volume32
Issue number4
DOIs
StatePublished - Jan 24 2013

Fingerprint

Clusterin
Bystander Effect
Ionizing Radiation
Insulin-Like Growth Factor I
Survival
Colon
Bone Marrow
Radioactive Hazard Release
Nuclear Weapons
Firefly Luciferases
Molecular Chaperones
Cytotoxins
Transforming Growth Factors
Somatomedins
Wound Healing
Thymus Gland
Breast
Spleen
Apoptosis
Antibodies

Keywords

  • bystander effects
  • insulin-like growth factor-1
  • low-dose ionizing radiation
  • p53 suppression
  • secretory clusterin
  • TGFβ1

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

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. / Klokov, D.; Leskov, K.; Araki, S.; Zou, Y.; Goetz, E. M.; Luo, X.; Willson, D.; Boothman, D. A.

In: Oncogene, Vol. 32, No. 4, 24.01.2013, p. 479-490.

Research output: Contribution to journalArticle

Klokov, D. ; Leskov, K. ; Araki, S. ; Zou, Y. ; Goetz, E. M. ; Luo, X. ; Willson, D. ; Boothman, D. A. / 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. In: Oncogene. 2013 ; Vol. 32, No. 4. pp. 479-490.
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