TGF-β signaling plays an important role in resisting γ-irradiation

An, You Sun; Kim, Mi Ra; Lee, Seung Sook; Lee, Yun Sil; Chung, Eun-Kyung; Song, Jie‐Young; Lee, Jeeyong; Yi, Jianxun

doi:10.1016/j.yexcr.2012.12.008

Cited by 16 publications

(12 citation statements)

References 26 publications

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“…Many of the deregulated miRNAs in our study are not yet fully characterized and additional investigations will likely provide more insights into their potential involvement in radiation responses. Many of the molecular pathways identified by the miRPath tool in irradiated mice fed a normal diet were known to be associated with radiation responses and/or cancer, such as the TGF-β [93], MAPK [94], ErbB [95] and Wnt [53] signaling pathways, apoptosis, etc. Interestingly, these radiation-induced miRNA regulations were not observed in irradiated obese mice.…”

Section: Discussionmentioning

confidence: 99%

Diet-Induced Obesity Modulates Epigenetic Responses to Ionizing Radiation in Mice

Varès¹,

Wang²,

Ishii-Ohba³

et al. 2014

PLoS ONE

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Both exposure to ionizing radiation and obesity have been associated with various pathologies including cancer. There is a crucial need in better understanding the interactions between ionizing radiation effects (especially at low doses) and other risk factors, such as obesity. In order to evaluate radiation responses in obese animals, C3H and C57BL/6J mice fed a control normal fat or a high fat (HF) diet were exposed to fractionated doses of X-rays (0.75 Gy ×4). Bone marrow micronucleus assays did not suggest a modulation of radiation-induced genotoxicity by HF diet. Using MSP, we observed that the promoters of p16 and Dapk genes were methylated in the livers of C57BL/6J mice fed a HF diet (irradiated and non-irradiated); Mgmt promoter was methylated in irradiated and/or HF diet-fed mice. In addition, methylation PCR arrays identified Ep300 and Socs1 (whose promoters exhibited higher methylation levels in non-irradiated HF diet-fed mice) as potential targets for further studies. We then compared microRNA regulations after radiation exposure in the livers of C57BL/6J mice fed a normal or an HF diet, using microRNA arrays. Interestingly, radiation-triggered microRNA regulations observed in normal mice were not observed in obese mice. miR-466e was upregulated in non-irradiated obese mice. In vitro free fatty acid (palmitic acid, oleic acid) administration sensitized AML12 mouse liver cells to ionizing radiation, but the inhibition of miR-466e counteracted this radio-sensitization, suggesting that the modulation of radiation responses by diet-induced obesity might involve miR-466e expression. All together, our results suggested the existence of dietary effects on radiation responses (especially epigenetic regulations) in mice, possibly in relationship with obesity-induced chronic oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Diet-Induced Obesity Modulates Epigenetic Responses to Ionizing Radiation in Mice

Varès¹,

Wang²,

Ishii-Ohba³

et al. 2014

PLoS ONE

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“…N‐terminally Flag‐tagged Smad2EE (S2EE) and Smad3EE (S3EE) constructs were generated by replacing the serine residues at 465/467 and 423/425, respectively, in the C‐terminus with glutamic acid [An et al, ]. Hemagglutinin (HA)‐tagged, truncated HSP90 (ΔHSP90) containing a C‐terminal amino acid (EEVD) deletion was kindly provided by Dr. S.W.…”

Section: Methodsmentioning

confidence: 99%

Heat Shock Protein 90 Regulates Subcellular Localization of Smads in Mv1Lu Cells

Lee

Kim

et al. 2015

J of Cellular Biochemistry

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Heat shock protein 90 (HSP90) regulates the stability of various proteins and plays an essential role in cellular homeostasis. Many client proteins of HSP90 are involved in cell growth, survival, and migration; processes that are generally accepted as participants in tumorigenesis. HSP90 is also up-regulated in certain tumors. Indeed, the inhibition of HSP90 is known to be effective in cancer treatment. Recently, studies showed that HSP90 regulates transforming growth factor β1 (TGF-β1)-induced transcription by increasing the stability of the TGF-β receptor. TGF-β signaling also has been implicated in cancer, suggesting the possibility that TGF-β1 and HSP90 function cooperatively during the cancer cell progression. Here in this paper, we investigated the role of HSP90 in TGF-β1-stimulated Mv1Lu cells. Treatment of Mv1Lu cells with the HSP90 inhibitor, 17-allylamino-demethoxy-geldanamycin (17AAG), or transfection with truncated HSP90 (ΔHSP90) significantly reduced TGF-β1-induced cell migration. Pretreatment with 17AAG or transfection with ΔHSP90 also reduced the levels of phosphorylated Smad2 and Smad3. In addition, the HSP90 inhibition interfered the nuclear localization of Smads induced by constitutively active Smad2 (S2EE) or Smad3 (S3EE). We also found that the HSP90 inhibition decreased the protein level of importin-β1 which is known to regulate R-Smad nuclear translocation. These data clearly demonstrate a novel function of HSP90; HSP90 modulates TGF-β signaling by regulating Smads localization. Overall, our data could provide a detailed mechanism linking HSP90 and TGF-β signaling. The extension of our understanding of HSP90 would offer a better strategy for treating cancer.

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“…Besides, TGF-β signaling is a good modifier of radiation responses and plays an important role in protecting cells from radiation [81]. Inducing the function of TGF-β receptor or constitutively activating SMAD family will reduce DNA fragmentation, Caspase-3 cleavage and γH2AX foci formation in irradiated cells [82]. Meanwhile, owing to the protection of TGF-β under radiation, there will be a decreased DNA damage, reduced apoptosis and thereby an enhanced cell survival rate [83].…”

Section: Mirna and The Midstream Transducers Of Radiation Related mentioning

confidence: 99%

MicroRNA and signal transduction pathways in tumor radiation response

Zhao

Cao

2013

Cellular Signalling

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Tumor radiation response is an essential issue in radiotherapy and a core determining factor of tumor radioresistance or radiosensitivity. Multiple factors can influence tumor radiation response, and among them tumor genetic and epigenetic background, tumor microenvironment and tumor blood flow status may take a leading role. During the whole process of tumor radiation response, tumor radiosensitivity can be regulated in an orderly manner through some classical signal transduction pathways. Although these pathways have already owned multiple biological functions and involved in the process of carcinogenesis, their regulatory roles in tumor radiation response can not be ignored. MicroRNA (miRNA) is a class of non-coding RNA of about 22 nucleotides in length, which binds to the 3’-untranslated region (3’-UTR) of target gene and controls the expression of it at the post-transcriptional level. MiRNA participates in numerous physiology and pathology processes and acts as oncogene or tumor suppressor to affect cancer progression. Through interplaying with the key components in radiation related signal transduction pathways, miRNA could effectively activate the expression of DNA damage response genes and cell cycle related genes in nucleus, and play a critical role in the modulation of radiation response and radiosensitivity in tumor cells. In this review, we mainly elucidate the regulatory mechanisms and functions of miRNA in these radiation related signal transduction pathways from three different aspects which include the upstream receptors, midstream transducer pathways, and downstream effector genes.

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TGF-β signaling plays an important role in resisting γ-irradiation

Cited by 16 publications

References 26 publications

Diet-Induced Obesity Modulates Epigenetic Responses to Ionizing Radiation in Mice

Diet-Induced Obesity Modulates Epigenetic Responses to Ionizing Radiation in Mice

Heat Shock Protein 90 Regulates Subcellular Localization of Smads in Mv1Lu Cells

MicroRNA and signal transduction pathways in tumor radiation response

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