• BMB Reports
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• v.53 no.11
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• pp.551-564
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• 2020

Proper development of the nervous system is critical for its function, and deficits in neural development have been implicated in many brain disorders. A precise and predictable developmental schedule requires highly coordinated gene expression programs that orchestrate the dynamics of the developing brain. Especially, recent discoveries have been showing that various mRNA chemical modifications can affect RNA metabolism including decay, transport, splicing, and translation in cell type- and tissue-specific manner, leading to the emergence of the field of epitranscriptomics. Moreover, accumulating evidences showed that certain types of RNA modifications are predominantly found in the developing brain and their dysregulation disrupts not only the developmental processes, but also neuronal activities, suggesting that epitranscriptomic mechanisms play critical post-transcriptional regulatory roles in development of the brain and etiology of brain disorders. Here, we review recent advances in our understanding of molecular regulation on transcriptome plasticity by RNA modifications in neurodevelopment and how alterations in these RNA regulatory programs lead to human brain disorders.

• Journal of Microbiology and Biotechnology
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• v.24 no.2
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• pp.287-294
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• 2014

The transcription factor E2F1 is active during G1 to S transition and is involved in the cell cycle and progression. A recent study reported that increased E2F1 is associated with DNA damage and tumor development in several tissues using transgenic models. Here, we show that E2F1 expression is regulated by tristetraprolin (TTP) in prostate cancer. Overexpression of TTP decreased the stability of E2F1 mRNA and the expression level of E2F1. In contrast, inhibition of TTP using siRNA increased the E2F1 expression. E2F1 mRNA contains three AREs within the 3'UTR, and TTP destabilized a luciferase mRNA that contained the E2F1 mRNA 3'UTR. Analyses of point mutants of the E2F1 mRNA 3'UTR demonstrated that ARE2 was mostly responsible for the TTP-mediated destabilization of E2F1 mRNA. RNA EMSA revealed that TTP binds directly to the E2F1 mRNA 3'UTR of ARE2. Moreover, treatment with siRNA against TTP increased the proliferation of PC3 human prostate cancer cells. Taken together, these results demonstrate that E2F1 mRNA is a physiological target of TTP and suggests that TTP controls proliferation as well as migration and invasion through the regulation of E2F1 mRNA stability.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7719-7724
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• 2013

Background: Overexpression of survivin, a known inhibitor of apoptosis, is associated with tumor progression and drug resistance in numerous malignancies, including leukemias. The aim of this study was to investigate the effect of a specific survivin small interference RNA (siRNA) on proliferation and the sensitivity of HL-60 acute myeloid leukemia (AML) cells to the chemotherapeutic drug etoposide. Materials and Methods: The cells were transfected with siRNAs using Lipofectamine $^{TM}2000$ transfection reagent. Relative survivin mRNA and protein levels were measured by quantitative real-time PCR and Western blotting, respectively. Trypan blue exclusion assays were performed to monitor tumor cell proliferation after siRNA transfection. The cytotoxic effects of etoposide and survivin siRNA, alone and in combination, on leukemic cells were determined using MTT assay. Apoptosis was assessed by ELISA cell death assay. Results: Survivin siRNA markedly reduced both mRNA and protein expression levels in a time-dependent manner, leading to distinct inhibition of cell proliferation and increased spontaneous apoptosis. Surprisingly, survivin siRNA synergistically increased the cell toxic effects of etoposide. Moreover, survivin down-regulation significantly enhanced its induction of apoptosis. Conclusions: Our study suggests that down-regulation of survivin by siRNA can trigger apoptosis and overcome drug resistance of leukemia cells. Therefore, survivin siRNA may be an effective adjuvant in AML chemotherapy.

• Animal cells and systems
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• v.1 no.1
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• pp.115-121
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• 1997

To precisely analyze the role of ovarian steroids in the regulation of laminin chain gene expression in mouse uterine tissues, the ovariectomized mouse model was used. Ovariectomized mice received a single injection of steroid hormones and total RNA was isolated from whole uterine tissues. Messenger RNA levels of each laminin chain (A, 81, and 82) were determined by competitive RT-peR procedures. Estradiol decreased mRNA levels of laminin 81 chain about two-fold, and 82 chain rather moderately. Estradiol-induced inhibition of laminin 81 and 82 chain mRNA levels were completely blocked by pretreatment with estrogen receptor antagonist tamoxifen. Estriol, a short acting estrogen which cannot induce hyperplastic responses of rodent uterine tissues, also showed an inhibitory effect on 81 and 82 chain mRNA levels, while estrone, an inactive estrogen, failed to influence either 8 chain mRNA levels. Effects of steroids on A chain mRNA level were quite different from those on 8 chains. Laminin A chain mRNA level was slightly increased by estradiol treatment, but negatively affected by progesterone. Progesterone treatment greatly increased both 8 chain mRNA levels, but slightly decreased A chain mRNA level compared to the control. The effect of progesterone on laminin chain-specific mRNA levels was further increased by co-injection of estradiol in a time-dependent manner. Progesterone-induced 81 and 82 chain mRNA transcription was inhibited by RU486, a synthetic anti-progesterone /anti-glucocorticoid. The present study demonstrates for the first time that steroids are able to regulate laminin gene expression in mouse uterine tissues, indicating that steroid-regulated laminin gene expression is involved in uterine growth and probably differentiation.

• Proceedings of the Korean Information Science Society Conference
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• 2006.06a
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• pp.67-69
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• 2006

MicroRNA (miRNA)는 생체내에서 gene regulation에 관여하는 핵심 small RNA 중 하나이다. miRNA는 Primary miRNA, Precursor miRNA, mature miRNA의 과정으로 processing 된다. miRNA 최종 형태인 mature miRNA의 정확한 위치 예측은 miRNA 예측의 필수적인 부분이다. 본 논문에서는, 진화적 최적화 예측 모델 중 하나인 유전 알고리즘을 이용하여 mature miRNA의 정확한 위치 예측을 수행한다. 제시된 방법은 이미 알려진 mature miRNA 위치를 positive example로 하고 임의로 생성한 위치를 negative example로 하여 서로의 linear scoring function 적합성 함수의 값 차이가 최대한으로 되도록 예측 모델을 진화시킨다. 유전 알고리즘을 이용한 진화적 최적화 모델로부터 mature miRNA 위치 예측에서 약 1.7nt 오차를 보여 기존의 방법 보다 개선된 성능을 보인다.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.629-635
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• 2014

Background: Acute myeloid leukemia (AML) is a fatal hematological malignancy which is resistant to a variety of chemotherapy drugs. Myeloid cell leukemia-1 (Mcl-1), a death-inhibiting protein that regulates apoptosis, has been shown to be overexpressed in numerous malignancies. In addition, it has been demonstrated that the expression level of the Mcl-1 gene increases at the time of leukemic relapse following chemotherapy. The aim of this study was to target Mcl-1 by small interference RNA (siRNA) and analyze its effects on survival and chemosensitivity of acute myeloid leukemia cell line HL-60. Materials and Methods: siRNA transfection was performed with a liposome approach. The expression levels of mRNA and protein were measured by real-time quantitative PCR and Western blot analysis, respectively. Trypan blue assays were performed to evaluate tumor cell growth after siRNA transfection. The cytotoxic effects of Mcl-1 siRNA (siMcl-1) and etoposide were determined using MTT assay on their own and in combination. Apoptosis was quantified using a DNA-histone ELISA assay. Results: Transfection with siMcl-1 significantly suppressed the expression of Mcl-1 mRNA and protein in a time-dependent manner, resulting in strong growth inhibition and spontaneous apoptosis. Surprisingly, pretreatment with siMcl-1 synergistically enhanced the cytotoxic effect of etoposide. Furthermore, Mcl-1 down-regulation significantly increased apoptosis sensitivity to etoposide. No significant biological effects were observed with negative control siRNA treatment. Conclusions: Our results suggest that specific suppression of Mcl-1 by siRNA can effectively induce apoptosis and overcome chemoresistance of leukemic cells. Therefore, siMcl-1 may be a potent adjuvant in leukemia chemotherapy.

• Korean Journal of Microbiology
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• v.46 no.3
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• pp.229-232
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• 2010

Enolase is one of the glycolytic enzymes, which are involved in a central energy metabolism present in nearly all organisms. In Escherichia coli, enolase constitutes RNA degradosome with RNase E, PNPase and RNA helicase, which are involved in most mRNA degradation and RNA processing. Recently, it has been reported that RNase G, an RNase E homolog, degrades eno mRNA. To examine a functional role of RNase G in enolase expression which is known to be up-regulated under microaerobic condition, we carried out experiments. Here, we report that expression levels of enolase and RNase G are not correlated under microaerobic condition. Based on this observation, we suggest the existence of an unknown factor(s) which regulate the activity of RNase G or enolase mRNA under microaerobic conditions.

• Archives of Pharmacal Research
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• v.27 no.4
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• pp.396-401
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• 2004

The effects of lipopolysaccharide (LPS) and several cytokines or the c-fos and c-jun mRNA expression were examined in primary cultured astrocytes. Either LPS (500 ng/mL) or inter-feron-$\gamma$ (IFN-$\gamma$ 5 ng/mL) alone increased the level of c-fos mRNA (1 h). However, tumor necro-sis factor-$\alpha$ (TNF-$\alpha$; 10 ng/mL) or interleukin-4 (IL-1$\beta$: 5 ng/mL) alone showed no significant induction of the level of c-fos mRNA. TNF-$\alpha$ showed a potentiating effect in the regulation of LPS-induced c-fos mRNA expression, whereas LPS showed an inhibitory action against IFN-Y-induced c-fos mRNA expression. LPS, but not TNF-$\alpha$, IL-1$\beta$ and IFN-$\gamma$, increased the level of c-jun mRNA (1 h). TNF-$\alpha$ and IFN-$\gamma$ showed an inhibitory action against LPS-induced c-jun mRNA expression. Both phorbol 12-myristate 13-acetate (PMA; 2.5 mM) and forskolin (FSK, 5 mM) increased the c-fos and c-jun mRNA expressions. In addition, the level of c-fos mRNA was expressed in an antagonistic manner when LPS was combined with PMA. When LPS was co-treated with either PMA or FSK, it showed an additive interaction for the induction of c-jun mRNA expression. Our results suggest that LPS and cytokines may be actively involved in the regulation of c-fos and c-jun mRNA expressions in primary cultured astrocytes. Moreover, both the PKA and PKC pathways may regulate the LPS-induced c-fos and c-jun mRNA expressions in different ways.

• Development and Reproduction
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• v.19 no.1
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• pp.11-17
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• 2015

This study investigated possible involvement of photoperiodic regulation in reproductive endocrine system of female olive flounder. To investigate the influence on brain-pituitary axis in endocrine system by regulating photoperiod, compared expression level of Kisspeptin and sbGnRH mRNA in brain and FSH-${\beta}$, LH-${\beta}$ and GH mRNA in pituitary before and after spawning. Photoperiod was treated natural photoperiod and long photoperiod (15L:9D) conditions from Aug. 2013 to Jun. 2014. Continuous long photoperiod treatment from Aug. (post-spawning phase) was inhibited gonadal development of female olive flounder. In natural photoperiod group, the Kiss2 expression level a significant declined in Mar. (spawning period). And also, FSH-${\beta}$, LH-${\beta}$ and GH mRNA expression levels were increasing at this period. However, in long photoperiod group, hypothalamic Kiss2, FSH-${\beta}$, LH-${\beta}$ and GH mRNA expression levels did not show any significant fluctuation. These results suggest that expression of hypothalamic Kiss2, GtH and GH in the pituitary would change in response to photoperiod and their possible involvement of photoperiodic regulation in reproductive endocrine system of the BPG axis.

• IMMUNE NETWORK
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• v.11 no.1
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• pp.11-41
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• 2011

The discovery of microRNA (miRNA) is one of the major scientific breakthroughs in recent years and has revolutionized current cell biology and medical science. miRNAs are small (19~25nt) noncoding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3' untranslated region (3'UTR) of specific messenger RNAs (mRNAs) for degradation of translation repression. Genetic ablation of the miRNA machinery, as well as loss or degradation of certain individual miRNAs, severely compromises immune development and response, and can lead to immune disorders. Several sophisticated regulatory mechanisms are used to maintain immune homeostasis. Regulatory T (Treg) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. Recent publications have provided compelling evidence that miRNAs are highly expressed in Treg cells, that the expression of Foxp3 is controlled by miRNAs and that a range of miRNAs are involved in the regulation of immunity. A large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as cancer, cardiovascular disease and diabetes, as well as psychiatric and neurological diseases. Although it is still unclear how miRNA controls Treg cell development and function, recent studies certainly indicate that this topic will be the subject of further research. The specific circulating miRNA species may also be useful for the diagnosis, classification, prognosis of diseases and prediction of the therapeutic response. An explosive literature has focussed on the role of miRNA. In this review, I briefly summarize the current studies about the role of miRNAs in Treg cells and in the regulation of the innate and adaptive immune response. I also review the explosive current studies about clinical application of miRNA.