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
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
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DOI：
10.1038/onc.2012.64
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发表时间：
2013-01-24
期刊：
影响因子：
8
通讯作者：
Boothman, D. A.
中科院分区：
文献类型：
--
作者：
Klokov, D.;Leskov, K.;Boothman, D. A.
在辐射事故、放射性污染地区的修复、太空旅行或脏弹之后，哺乳动物组织无意中暴露在低剂量的电离辐射(IR)中，这对生物体来说是一种有趣的创伤。可能的低剂量IR诱导的旁观者效应可能会影响我们对人类健康影响的评估，因为在IR=2cGy剂量照射后，组织内的细胞受到不同程度的损害，诱导的hCLUp-Luc活性在96h达到峰值，与内源性sCLU水平一致。随着剂量的增加(~gt；=1Gy)，sCLU的诱导幅度增加，到达峰值的时间减少。胰岛素样生长因子-1刺激sCLU的表达，而p53抑制sCLU的表达。转基因hCLUp-Luc报告基因小鼠对低剂量IR的反应表明，雌性小鼠的特定组织(即结肠、脾、乳腺、胸腺和骨髓)在全身(~gt；=10cGy)照射后诱导的hCLUp-Luc活性高于雄性小鼠。HCLUp-Luc和内源性sCLU水平的组织特异性、非线性剂量和时间反应被记录下来。结肠在10cGy后维持内环境平衡。骨髓的反应是表达延迟，但延长和升高。在IR暴露后立即腹腔注射α-转化生长因子β1(1D11)，而不是对照抗体(13C4)，可消除CLU诱导反应。在体诱导也与IR后激活的转化生长因子β1激活的Smad信号有关。从机制上讲，sCLU水平升高的培养液抑制了信号传递，阻止了细胞凋亡，并提高了暴露于转化生长因子β1的肿瘤或正常细胞的存活率。因此，sCLU是一种支持生存的旁观者因子，它取消了转化生长因子β1信号转导，最有可能促进伤口愈合。Oncogene(2013年)32479490；doi：10.1038/onc.2012.64；2012年3月5日在线发布
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 = 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 alpha-transforming growth factor (TGF)beta 1 (1D11), but not control (13C4) antibodies, immediately following IR exposure abrogated CLU induction responses. Induction in vivo also correlated with Smad signaling by activated TGF beta 1 after IR. Mechanistically, media with elevated sCLU levels suppressed signaling, blocked apoptosis and increased survival of TGF beta 1-exposed tumor or normal cells. Thus, sCLU is a pro-survival bystander factor that abrogates TGF beta 1 signaling and most likely promotes wound healing. Oncogene (2013) 32, 479-490; doi:10.1038/onc.2012.64; published online 5 March 2012