• The Korean Journal of Physiology and Pharmacology
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• v.14 no.2
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• pp.91-97
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• 2010

Epidermal keratinocytes overgrow in response to ultraviolet-B (UVB), which may be associated with skin photoaging and cancer development. Recently, we found that HIF-$1{\alpha}$ controls the keratinocyte cell cycle and thereby contributes to epidermal homeostasis. A further study demonstrated that HIF-$1{\alpha}$ is down-regulated by UVB and that this process is involved in UVB-induce skin hyperplasia. Therefore, we hypothesized that the forced expression of HIF-$1{\alpha}$ in keratinocytes would prevent UVB-induced keratinocyte overgrowth. Among several agents known to induce HIF-$1{\alpha}$, pyrithione-zinc (Py-Zn) overcame the UVB suppression of HIF-$1{\alpha}$ in cultured keratinocytes. Mechanistically, Py-Zn blocked the degradation of HIF-$1{\alpha}$ protein in keratinocytes, while it did not affect the synthesis of HIF-$1{\alpha}$. Moreover, the p21 cell cycle inhibitor was down-regulated after UVB exposure, but was robustly induced by Py-Zn. In mice repeatedly irradiated with UVB, the epidermis became hyperplastic and HIF-$1{\alpha}$ disappeared from nuclei of epidermal keratinocytes. However, a cream containing Py-Zn effectively prevented the skin thickening and up-regulated HIF-$1{\alpha}$ to the normal level. These results suggest that Py-Zn is a potential agent to prevent UVB-induced photoaging and skin cancer development. This work also provides insight into a molecular target for treatment of UVB-induced skin diseases.

• Toxicological Research
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• v.24 no.2
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• pp.101-107
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• 2008

Studies on hypoxia-signaling pathways have revealed novel Fe(II) and $\alpha$-ketoglutarate-dependent dioxygenases that hydroxylate prolyl or asparaginyl residues of a transactivator, Hypoxia-Inducible $Factor-\alpha(HIF-\alpha)$ protein. The recognition of these unprecedented dioxygenases has led to open a new paradigm that the hydroxylation mediates an instant post-translational modification of a protein in response to the changes in cellular concentrations of oxygen, reducing agents, or $\alpha$-ketoglutarate. Activity of $HIF-\alpha$ is repressed by two hydroxylases. One is $HIF-\alpha$ specific prolyl-hydroxylases, referred as prolyl-hydroxylase domain(PHD). The other is $HIF-\alpha$ specific asparaginyl-hydroxylase, referred as factor-inhibiting HIF-1(FIH-1). The facts (i) that many dioxygenases commonly use molecular oxygen and reducing agents during detoxification of xenobiotics, (ii) that detoxification reaction produces radicals and reactive oxygen species, and (iii) that activities of both PHD and FIH-1 are regulated by the changes in the balance between oxygen species and reducing agents, imply the possibility that the activity of $HIF-\alpha$ can be increased during detoxification process. The importance of $HIF-\alpha$ in cancer and ischemic diseases has been emphasized since its target genes mediate various hypoxic responses including angiogenesis, erythropoiesis, glycolysis, pH balance, metastasis, invasion and cell survival. Therefore, activators of PHDs and FIH-1 can be potential anticancer drugs which could reduce the activity of HIF, whereas inhibitors, for preventing ischemic diseases. This review highlights these novel dioxygenases, PHDs and FIH-1 as specific target against not only cancers but also ischemic diseases.

• Proceedings of the KIEE Conference
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• 1999.07c
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• pp.1373-1375
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• 1999

High impedance fault (HIF) is defined as fault the general overcurrent relay can not detect or interrupt. Especially when HIF occur in residential areas, energized high voltage conductor results in fire hazard, equiment damage or personal threat. This paper proposes the model of HIF in transmission line using the ZnO arrester and resistance to be implemented within EMTP. Wavelet transform is efficient and useful for the detection of HIF in power system, because it uses variable windows according to frequency. HIF detection method using wavelet transform can distinguish HIF from similar phenomena like arcfurance load, capacitor bank switching and line switching.

• Journal of Marine Bioscience and Biotechnology
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• v.7 no.2
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• pp.35-41
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• 2015

Whales are marine mammals that are fully adapted to aquatic environment. Whales breathe by lungs so they require adaptive system to low oxygen concentration (hypoxia) while deep and prolonged diving. However, the study for the molecular mechanism underlying cetacean adaptation to hypoxia has been limited. Hypoxia-inducible factor (HIF) is the central transcription factor that regulates hypoxia-related gene expression. Here we identified HIF-binding sites in whale genome by phylogenetic footprinting and analyzed HIF-target genes to understand how whales cope with hypoxia. By comparison with the HIF-target genes of terrestrial mammals, it was suggested that whales may retain unique adaptation mechanisms to hypoxia.

• Proceedings of the KIEE Conference
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• 1997.07c
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• pp.924-926
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• 1997

A high impedance fault(HIF) in a power system could be due to a downed conductor, and is a dangerous situation because the current may be too small to be detected by conventional means. In this paper, HIF(High impedance fault) and LIF(Low impedance fault) detection methods were reviewed. No single defection method can detect all electrical conditions resulting from downed conductor faults, because high impedance fault have arc phenomena, asymmetry and randomness. Neural network are well-suited for solving difficult signal processing and pattern recognition problem. This paper presents the application of artificial neural network(ANN) to detect the HIF and LIF. Test results show that the neural network was able to identify the high impedance fault by real-time operation. Furthermore, neural network was able to discriminate the HIF from the LIF.

• Molecules and Cells
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• v.44 no.10
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• pp.710-722
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• 2021

Hypoxia, or low oxygen tension, is a hallmark of the tumor microenvironment. The hypoxia-inducible factor-1α (HIF-1α) subunit plays a critical role in the adaptive cellular response of hypoxic tumor cells to low oxygen tension by activating gene-expression programs that control cancer cell metabolism, angiogenesis, and therapy resistance. Phosphorylation is involved in the stabilization and regulation of HIF-1α transcriptional activity. HIF-1α is activated by several factors, including the mitogen-activated protein kinase (MAPK) superfamily. MAPK phosphatase 3 (MKP-3) is a cytoplasmic dual-specificity phosphatase specific for extracellular signal-regulated kinase 1/2 (Erk1/2). Recent evidence indicates that hypoxia increases the endogenous levels of both MKP-3 mRNA and protein. However, its role in the response of cells to hypoxia is poorly understood. Herein, we demonstrated that small-interfering RNA (siRNA)-mediated knockdown of MKP-3 enhanced HIF-1α (not HIF-2α) levels. Conversely, MKP-3 overexpression suppressed HIF-1α (not HIF-2α) levels, as well as the expression levels of hypoxia-responsive genes (LDHA, CA9, GLUT-1, and VEGF), in hypoxic colon cancer cells. These findings indicated that MKP-3, induced by HIF-1α in hypoxia, negatively regulates HIF-1α protein levels and hypoxia-responsive genes. However, we also found that long-term hypoxia (>12 h) induced proteasomal degradation of MKP-3 in a lactic acid-dependent manner. Taken together, MKP-3 expression is modulated by the hypoxic conditions prevailing in colon cancer, and plays a role in cellular adaptation to tumor hypoxia and tumor progression. Thus, MKP-3 may serve as a potential therapeutic target for colon cancer treatment.

• Biomolecules & Therapeutics
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• v.13 no.4
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• pp.227-231
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• 2005

The estrogen receptor (ER) is activated and degraded by estrogen. We have examined ER downregulation and activation under hypoxia mimetic conditions. Cobalt chloride induced ER downregulation at 24 h of treatment. This degradation involved hypoxia-inducible factor-1$\alpha$ (HIF-1$\alpha$) as examined by using a constitutively active form of HIF-1$\alpha$, HIF-1$\alpha$/VP16, constructed by replacing the transactivation domain of HIF-1$\alpha$ with that of VP16. Western blot analysis revealed that E2-induced ER downregulation was observed within ${\~}6h$, whereas HIF-1$\alpha$/VP16-induced ER degradation was observed within 12${\~}$20h. HIF-1$\alpha$/VP16 activated the transcription of estrogen-responsive reporter gene in the absence of estrogen. These results suggest that ER downregulation and activation under hypoxia maybe mediated in part by a HIP-1$\alpha$ expression.

• Journal of Electrical Engineering and Technology
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• v.8 no.6
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• pp.1520-1529
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• 2013

In this paper, we propose and assess the performance of "H infinity filter ($H_{\infty}$, HIF)" and "cost reference particle filter (CRPF)" in the problem of tracking a target based on the measurements of the range and the bearing of the target. HIF and CRPF have the common advantageous feature that we do not need to know the noise statistics of the problem in their applications. The performance of the extended Kalman filter (EKF) is also compared with that of the proposed filters, but the noise information is perfectly known for the applications of the EKF. Simulation results show that CRPF outperforms HIF, and is more robust because the tracking of HIF diverges sometimes, particularly when the target track is highly nonlinear. Interestingly, when the tracking of HIF diverges, the tracking of the EKF also tends to deviate significantly from the true track for the same target track. Therefore, CRPF is very effective and appropriate approach to the problems of highly nonlinear model, especially when the noise statistics are unknown. Nonetheless, HIF also can be applied to the problem of timevarying state estimation as the EKF, particularly for the case when the noise statistcs are unknown. This paper provides a good example of how to apply CRPF and HIF to the estimation of dynamically varying and nonlinearly modeled states with unknown noise statistics.

• Genomics & Informatics
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• v.6 no.2
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• pp.72-76
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• 2008

Hypoxia-inducible factor $1{\alpha}\;(HIF1{\alpha})$ is a transcription factor that plays a key role in the adaptation of cells to low oxygen stress and oxygen homeostasis. The oxygen-dependent degradation (ODD) domain of $HIF1{\alpha}$ is responsible for the negative regulation of $HIF1{\alpha}$ in normoxia. The interactions of the $HIF1{\alpha}$ ODD domain with partner proteins such as von Hippel-Lindau tumor suppressor (pVHL) and p53 are mediated by two sequence motifs, the N- and C-terminal ODD(NODD and CODD). Multiple sequence alignment with $HIF1{\alpha}$ homologs from human, monkey, pig, rat, mouse, chicken, frog, and zebrafish has demonstrated that the NODD and CODD motifs have noticeably high conservation of the primary sequence across different species and isoforms. In this study, we carried out molecular dynamics simulation of the structure of the $HIF1{\alpha}$ CODD motif in complex with the p53 DNA-binding domain (DBD). The structure reveals specific functional roles of highly conserved residues in the CODD sequence motif of $HIF1{\alpha}$ for the recognition of p53.

• Proceedings of the KAIS Fall Conference
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• 2009.05a
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• pp.227-230
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• 2009

목적 : 비소세포 폐암에서 HIF-$1{\alpha}$, VEGF의 발현과 예후와 관련된 여러 임상적 표지자 및 병리학적 표지자와의 상관관계를 조사하고자 하였다. 방법 : 이들의 예후인자로서의 의미를 알아보고자 외과적으로 절제한 44예의 비소세포 폐암종을 대상으로 VEGF, HIF-$1{\alpha}$에 대한 면역조직화학염색을 시행하였다. 결과 : WHO 분류에 의한 조직학적인 형태인 편평세포암종 28예, 선암종 16예의 비세포성 폐암이 이 연구에 포함되었다. 비소세포성 폐암 24예와 16예에서 VEGF 및 HIF-$1\alpha$이 발현되었다. 결론 : 이 연구에서 VEGF 발현과 병기와의 상관관계, HIF-$1{\alpha}$의 과발현과 병기 사이에서 통계적으로 유의한 상관관계를 볼 수 없었다. 또한 HIF-$1{\alpha}$의 과발현과 VEGF의 발현 사이에 통계학적으로 유의한 관련성이 없었다.