Nutlin-3 induces HO-1 expression by activating JNK in a transcription-independent manner of p53

CHOE, YUN-JEONG,LEE, SUN-YOUNG,KO, KYUNG WON,SHIN, SEOK JOON,KIM, HO-SHIK Spandidos Publications 2014 International journal of oncology Vol.44 No.3

A recent study reported that p53 can induce HO-1 by directly binding to the putative p53 responsive element in the HO-1 promoter. In this study, we report that nutlin-3, a small molecule antagonist of HDM2, induces the transcription of HO-1 in a transcription-independent manner of p53. Nutlin-3 induced HO-1 expression at the level of transcription in human cancer cells such as U2OS and RKO cells. This induction of HO-1 did not occur in SAOS cells in which p53 was mutated and was prevented by knocking down the p53 protein using p53 siRNA transfection, but not by PFT-alpha, an inhibitor of the transcriptional activity of p53. Accompanying HO-1 expression, nutlin-3 stimulated the accumulation of ROS and the phosphorylation of MAPKs such as JNK, p38 MAPK and ERK1/2. Nutlin-3-induced HO-1 expression was suppressed by TEMPO, a ROS scavenger, and chemical inhibitors of JNK and p38 MAPK but not ERK1/2. In addition, nutlin-3-induced phosphorylation of JNK but not p38 MAPK was inhibited by TEMPO. Notably, the levels of nutlin-3-induced ROS were correlated with the mitochondrial translocation of p53 and this induction was prevented by PFT-beta, an inhibitor of the mitochondrial translocation of p53. Consistent with the effect of the ROS scavenger and MAPK inhibitors, PFT-beta reduced HO-1 expression and the phosphorylation of JNK induced by nutlin-3. In the experiments of analyzing cell death, the knockdown of HO-1 augmented nutlin-3-induced apoptosis. Collectively, these results suggest that nutlin-3 induces HO-1 expression via the activation of both JNK which is dependent on ROS generated by p53 translocated to the mitochondria and p38 MAPK which appears to be stimulated by a ROS-independent mechanism, and this HO-1 induction may inhibit nutlin-3-induced apoptosis, constituting a negative feedback loop of p53-induced apoptosis.

PGA2-induced expression of HO-1 is mediated by transcriptional upregulation of Nrf2

Sang-sun Lee,Yun-Jeong Choe,Hyein Lee,Sun-Young Lee,Ho-Shik Kim 대한독성 유전단백체 학회 2019 Molecular & cellular toxicology Vol.15 No.2

Backgrounds: Prostaglandin (PG) A2 reportedly stimulated expression of heme oxygenase (HO)-1 at the level of transcription via the activation of p38MAPK. Details of the mechanism, however, have not been provided, and this includes identification of the transcription factors responsible for PGA2-induced HO-1 expression. Herein is described an analysis of the role of nuclear factor erythroid 2 related factor 2 (Nrf2) and how PGA2 increases the activity of Nrf2 during PGA2-induced HO-1 expression. Methods: Expressions of HO-1 and Nrf2 were analyzed at the levels of both mRNA and protein. Nrf2 siRNA, SB203580, an inhibitor of p38MAPK, and scavengers of reactive oxygen species (ROS) were used to identify the effects of Nrf2, p38MAPK and ROS on PGA2-induced HO-1 expression. Results: Although SB203580 suppressed PGA2-induced HO-1 expression, genetic activation of p38MAPK could not stimulate the transcription of HO-1. Cycloheximide (CHX), an inhibitor of protein translation, almost completely prevented PGA2-induced increase of HO-1 transcription, but it did not prevent the phosphorylation of p38MAPK, which suggests that both de novo protein synthesis and p38MAPK activity are required to induce the transcription of HO-1 in response to PGA2 treatment. In addition, PGA2 increased the level of both Nrf2 mRNA and protein in a dose-dependent manner. Knockdown of Nrf2 using small interfering RNA (siRNA) suppressed PGA2-induced HO-1 expression. The PGA2-induced transcription of Nrf2 was prevented by ROS scavengers such as n-acetyl-l-cysteine and tempol but not CHX. Furthermore, siRNA against p38MAPK did not change the level of nuclear Nrf2 protein. Conclusion: These findings suggest that PGA2 induces HO-1 transcription via an increase in Nrf2 protein, the transcription of which is initiated by an accumulation of ROS that is independent of the p38MAPK activation pathway.

PGA2 induces the expression of HO-1 by activating p53 in HCT116 cells

Hyein Lee,Sang-Sun Lee,Ji-Young Park,Yun-Jeong Choe,이선영,Ho-Shik Kim,H.-S. Kim 대한독성 유전단백체 학회 2017 Molecular & cellular toxicology Vol.13 No.2

Prostaglandin (PG) A2 which is a cytotoxic PG, was reported to induce the expression of heme oxygenase (HO)-1 via activation of p38MAPK to keep U2OS cells from cell cycle arrest in G2M phase. The expression of HO-1 is primarily regulated at the level of transcription. But the transcription factors that are responsible for PGA2-induced HO-1 expression were not clarified yet. Here, we report that PGA2-induced transcription of HO-1 is mediated by p53, a tumor suppressive transcription factor. In HCT116 cells, PGA2 treatment led to the phosphorylation of p53 and an increase of p21WAF1 transcription as well as the activation of HO-1 transcription. Knocking p53 down via RNA interference or inhibiting the p53’s transcriptional activity by pifithrin-α treatment led to suppression of the increase in the level of both HO-1 expression and activity of HO-1 promoter. Pretreatment of NU- 7441, a chemical inhibitor of DNA-activated protein kinase (DNA-PK), prevented both the PGA2-induced phosphorylation of p53 and an increase of HO-1 transcription. In addition, N-acetyl-l-cysteine, a scavenger of reactive oxygen species (ROS), also mimicked the effect of NU-7441 on the PGA2-induced activation of p53 and HO-1 transcription. Collectively, these results suggest that PGA2 induces the expression of HO-1 via activation of p53, which is mediated by the ROSDNA- PK pathway.

Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis <i>via</i> Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

Kim, Ji-Hee,Lee, Kwang-Soon,Lee, Dong-Keon,Kim, Joohwan,Kwak, Su-Nam,Ha, Kwon-Soo,Choe, Jongseon,Won, Moo-Ho,Cho, Byung-Ryul,Jeoung, Dooil,Lee, Hansoo,Kwon, Young-Guen,Kim, Young-Myeong Mary Ann Liebert 2014 Antioxidants & redox signaling Vol.21 No.18

<P>Aims: Hypoxia induces expression of various genes and microRNAs (miRs) that regulate angiogenesis and vascular function. In this study, we investigated a new functional role of new hypoxia-responsive miR-101 in angiogenesis and its underlying mechanism for regulating heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) expression. Results: We found that hypoxia induced miR-101, which binds to the 3 ' untranslated region of cullin 3 (Cul3) and stabilizes nuclear factor erythroid-derived 2-related factor 2 (Nrf2) via inhibition of the proteasomal degradation pathway. miR-101 overexpression promoted Nrf2 nuclear accumulation, which was accompanied with increases in HO-1 induction, VEGF expression, and endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production. The elevated NO-induced S-nitrosylation of Kelch-like ECH-associated protein 1 and subsequent induction of Nrf2-dependent HO-1 lead to further elevation of VEGF production via a positive feedback loop between the Nrf2/HO-1 and VEGF/eNOS axes. Moreover, miR-101 promoted angiogenic signals and angiogenesis both in vitro and in vivo, and these events were attenuated by inhibiting the biological activity of HO-1, VEGF, or eNOS. Moreover, these effects were also observed in aortic rings from HO-1(+/-) and eNOS(-/-) mice. Local overexpression of miR-101 improved therapeutic angiogenesis and perfusion recovery in the ischemic mouse hindlimb, whereas antagomiR-101 diminished regional blood flow. Innovation: Hypoxia-responsive miR-101 stimulates angiogenesis by activating the HO-1/VEGF/eNOS axis via Cul3 targeting. Thus, miR-101 is a novel angiomir. Conclusion: Our results provide new mechanistic insights into a functional role of miR-101 as a potential therapeutic target in angiogenesis and vascular remodeling. Antioxid. Redox Signal. 21, 2469-2482.</P>

복식자궁전적출술과 인공슬관절 치환술 환자에서 정맥내 자가통증조절이 수술 후 진통에 미치는 효과

최영균,남현옥,이정한,이근무,정순호,김영재,신치만 白中央醫療院 2005 仁濟醫學 Vol.26 No.1

Objective: Intravenous patient-controlled analgesia(IV PCA) is gaining wide spread popularity in the management of postoperative pain control. The purpose of this study is to evaluate the severity of pain after TAH and TKRA through comparing visual analogue scale(VAS) of pain of each patients who received identical IV PCA protocol, and to improve our IV PCA protocol. Methods: TAH group includes twenty female patients who were scheduled for TAH. TKRA group includes twenty female patients who were scheduled for TKRA. Each group received fentanyl 50㎍ about 30minutes before the end of surgery, followed by IV PCA with fentanyl 1500 ㎍, ketolorac 300mg, ondansteron 8mg, normal saline 56㎖(total 96ml, basal infusion rate 1㎖/hr, bolus dose 1㎖, lockout time 10 minutes). VAS scores were recorded at 1, 6, 12, 24, 48 hours postoperatively. Total bolus doses and patients' satisfaction were checked after the end of analgesia. Results: VAS scores of TKRA group were significantly higher than those of TAH group at 12, 24, 48 hours postoperatively. VAS scores of both group progressively decreased(P<0.05). Patients' satisfaction score showed no significant difference between two groups. Total bolus dose of TKRA group was significantly higher than that of TAH. Conclusion: The postoperative pain of TKRA was more severe than that of TAH. TKRA group needed more profound postoperative pain control than TAH group. We should consider the increase of early postoperative period analgesic doses to acquire optimal pain control of both group.

근치적 전립선 절제술 중에 Indigo Carmine 정주 후 발생한 심한 저혈압 : 증례 보고 A case report

최민호,김동찬,한영진,최훈 대한마취과학회 2002 Korean Journal of Anesthesiology Vol.43 No.3

극단 저체중 신생아에서의 동맥관 개존증 결찰술을 위한 진정맥 마취 경험 2례

최영균,고명진,이상은,조광래,김영환,임세훈,이정한,이근무,정순호,김영재,신치만 仁濟大學校 白病院 2010 仁濟醫學 Vol.31 No.-

Running title: Cases of anesthesia for extremely low birth weight infant. Extremely low birth weight infants (birth weight < 1000 g) are prone to various morbidities such as respiratory distress syndrome, intraventricular hemorrhage, periventricular leukomalacia, patent ductus arteriosus, necrotizing enterocolitis and retinopathy. To accomplish successful anesthetic management, many precautions must be continuously taken during the operation. First, inspired oxygen concentration should be adjusted to avoid oxygen toxicity. Second, body temperature must be maintained adequately. Third, hemodynamic parameters should be kept stable. We report 2 cases of successful anesthetic management for extremely low birth weight infant who underwent ligation of patent ductus arteriosus at the neonatal intensive care unit.

Nicardipine이 당뇨병성 자율신경병증 환자에서 기관내 삽관에 따른 혈역학적 변화에 미치는 영향

최민호,김동찬,한영진,최훈 대한마취과학회 2002 Korean Journal of Anesthesiology Vol.43 No.4

Background: A laryngoscopy and tracheal intubation often provoke an undesirable increase in blood pressure and heart rate. These hemodynamic responses to tracheal intubation in diabetics are blunted due to autonomic neuropathy. This study was designed to determine the optimal dose of nicardipine in diabetic autonomic neuropathy patients. Methods: According to the nicardipine dose, 80 diabetics were randomly allocated to four groups of 20 patients. Tracheal intubation by direct laryngoscopy was performed. After intravenous thiopental d mg/kg, vecuronium 0.13 mg/kg and one of the dosages of nicardipine 3, 5, or 7 ㎍/kg followed by mask ventilation of three minutes with enflurane, nitrous oxide and oxygen. Heart rate and blood pressure were mesured five times at one minute intervals. Results: There was no significant difference in the 3 ㎍/kg group compared with the control group. On the other hand, there was a sufficient blood pressure decrease in the ㎍/kg and 7 ㎍/kg group. However, in the 7 ㎍/kg group, 55% of cases showed severe hypotension (< 70 mmHg). Conchusions: We suggest that the appropriate dose of nicardipine for prevention of tachycardia, and hypertension in diabetic autonomic neuropathy patients is 5 ㎍/kg. (Korean J Anesthesiol 2002; 43: 436~442)

'탈인간의 심리학'과 자율적 주체의 운명

최호영 한국문화교육학회 2010 문화예술교육연구 Vol.5 No.2

인문학의 여러 분야에서 논의되고 있는 탈인간주의는 인간과 기계의 융합 경향 속에서 근대 인간관의 핵심인 '자율적 주체'의 운명을 문제 삼고 있다. 심리학은 19세기에 독립된 학문으로 성립된 이래로 인간을 자율적 존재로 보는 인문학적 접근과 인간을 결정된 존재로 보는 자연과학적 접근이 늘 병존해 왔다는 의미에서 이미 '탈인간의 심리학'이었다. 필자는 '자율적 주체'라는 관념이 우리가 목표지향적 행위자로서 살아가는 일상생활의 조직원리로서, 그리고 인간에 대한 인과적 지식에 의미를 부여하는 기본 개념틀로서 여전히 유효하다고 주장하였다. 그리고 문화와 문화교육은 과학기술이 인간의 목적합리성에서 벗어나지 않도록 성찰하고 조정하는 역할을 수행해야 한다고 주장하였다. The posthumanism, as it is discussed in several areas of the humanities, calls the modern humanist concept of autonomous subject into question. The scientific psychology has been since its birth as independent discipline at the 19th century a 'posthuman psychology' in the sense that there has been always humanistic approaches to humans as autonomous beings on the one hand, and natural-scientific approaches to humans as determined beings on the other hand. I have argued that the concept of autonomous subject makes still sense as a regulating principle of everyday life of purposive agents and as a conceptual framework for interpreting causal knowledges about humans. And I have argued that culture and cultural education should play an important role in reflecting on the meaning and rationality of sciences and technologies.

로렌스의『여우』 : 반외디프스 콤플렉스

최기군,정호영 조선대학교 외국문화연구소 1996 外國文化硏究 Vol.19 No.1

The Fox. one of D. H. Lawrence's representative shorter novels, is the most suitable work to approach his literary world in terms of the anti-Oedipus complex, that is to say, the relationship between the devouring mother and the child possessed with the matricide impulse. This paper aims to study Lawrence's anti-Oedipus complex by focusing on the complicated and subtle conflicts among the major characters in The Fox. Lawrence regards the relationship between Banford and Grenfel as a kind of mother-child relationship. He also includes the relationship between March and Grenfel in the larger sense of a mother-child relationship. Threatened by Banford, he decides to remove her, so to speak, as a devouring mother. In the end he succeeds in removing his opponent, yet he has to struggle with another devouring mother, March. The relation between mother-leadership and male power in The Fox is closely linked with a much larger issue, what is called Lawrence's leadership. In all his works written after World War I, he advocated male leadership as a means of resisting female leadership. In his real life he attempted in vain to resist the pressure that come from his dependency upon women by ruling them. In this regard, his wife, Frieda Lawrence, provides us with a crucial testimony. According to her, Lawrence always dreaded women, feeling that women were in the end more powerful than men. Ironically, Lawrence himself called his wife a devouring mother, who said, "Man is born from woman and returns to her for his ultimate needs of body and soul. and she is like earth and death to which all return." She is thought to have been Lawrence's worst and strongest enemy. In conclusion, Lawrence, having been overwhelmed by his mother in his childhood, grew up to advocate the male ascendancy in an effort to escape from his woman complex.