• 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.

• Biomolecules & Therapeutics
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• v.28 no.1
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• pp.45-57
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• 2020

In the neurovascular unit, the neuronal and vascular systems communicate with each other. O₂ and nutrients, reaching endothelial cells (ECs) through the blood stream, spread into neighboring cells, such as neural stem cells, and neurons. The proper function of neural circuits in adults requires sufficient O₂ and glucose for their metabolic demands through angiogenesis. In a central nervous system (CNS) injury, such as glioma, Parkinson's disease, and Alzheimer's disease, damaged ECs can contribute to tissue hypoxia and to the consequent disruption of neuronal functions and accelerated neurodegeneration. This review discusses the current evidence regarding the contribution of oxygen deprivation to CNS injury, with an emphasis on hypoxia-inducible factor (HIF)-mediated pathways and Notch signaling. Additionally, it focuses on adult neurological functions and angiogenesis, as well as pathological conditions in the CNS. Furthermore, the functional interplay between HIFs and Notch is demonstrated in pathophysiological conditions.

• BMB Reports
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• v.56 no.4
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• pp.252-257
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• 2023

The hypoxia-inducible factor-1α (HIF-1α) is a key regulator of hypoxic stress under physiological and pathological conditions. HIF-1α protein stability is tightly regulated by the ubiquitin-proteasome system (UPS) and autophagy in normoxia, hypoxia, and the tumor environment to mediate the hypoxic response. However, the mechanisms of how the UPS and autophagy interplay for HIF-1α proteostasis remain unclear. Here, we found a HIF-1α species propionylated at lysine (K) 709 by p300/CREB binding protein (CBP). HIF-1α stability and the choice of degradation pathway were affected by HIF-1α propionylation. K709-propionylation prevented HIF-1α from degradation through the UPS, while activated chaperon-mediated autophagy (CMA) induced the degradation of propionylated and nonpropionylated HIF-1α. CMA contributed to HIF-1α degradation in both normoxia and hypoxia. Furthermore, the pan-cancer analysis showed that CMA had a significant positive correlation with the hypoxic signatures, whereas SIRT1, responsible for K709-depropionylation correlated negatively with them. Altogether, our results revealed a novel mechanism of HIF-1α distribution into two different degradation pathways.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10393-10396
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• 2015

Background: Endometral carcinoma is the most common malignant tumor of the female genital tract and the fourth most common cancer in women after breast, colorectal and lung cancers Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor that regulates cellular response to hypoxia HIF-1 plays important roles in the development and progression of cancer through activation of various genes that are involved in crucial aspects of cancer biology, including angiogenesis, energy metabolism, vasomotor function, erythropoiesis, and cell survival. In this study, we aimed to investigate the association between HIF-1 1772 C/T polymorphisms and endometrial cancer. Materials and Methods: 75 patients with endometrial carcinoma and 75 patients whose underwent hysterectomy for non tumoral indication selected for evaluation of HIF-1 1772 C/T polymorphisms by PCR-RFLP and sequencing. Results: For the 1772 C/T polymorphism, the analysis showed that the T allele and genotype TT were significantly associated with endometrial cancer risk. Conclusions: Our results suggest that the C1772T polymorphism of the HIF-1a may be associated with endometrial cancers.

• Biomolecules & Therapeutics
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• v.20 no.3
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• pp.280-285
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• 2012

The developing embryo naturally experiences relatively low oxygen conditions in vivo. Under in vitro hypoxia, mouse embryonic stem cells (mESCs) lose their self-renewal activity and display an early differentiated morphology mediated by the hypoxia-inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$). Previously, we demonstrated that histone deacetylase (HDAC) is activated by hypoxia and increases the protein stability and transcriptional activity of HIF-$1{\alpha}$ in many human cancer cells. Furthermore HDAC1 and 3 mediate the differentiation of mECSs and hematopoietic stem cells. However, the role of HDACs and their inhibitors in hypoxia-induced early differentiation of mESCs remains largely unknown. Here, we examined the effects of several histone deacetylase inhibitors (HDACIs) on the self-renewal properties of mESCs under hypoxia. Inhibition of HDAC under hypoxia effectively decreased the HIF-$1{\alpha}$ protein levels and substantially improved the expression of the LIF-specific receptor (LIFR) and phosphorylated-STAT3 in mESCs. In particular, valproic acid (VPA), a pan HDACI, showed dramatic changes in HIF-$1{\alpha}$ protein levels and LIFR protein expression levels compared to other HDACIs, including sodium butyrate (SB), trichostatin A (TSA), and apicidin (AP). Importantly, our RT-PCR data and alkaline phosphatase assays indicate that VPA helps to maintain the self-renewal activity of mESCs under hypoxia. Taken together, these results suggest that VPA may block the early differentiation of mESCs under hypoxia via the destabilization of HIF-$1{\alpha}$.

• The Journal of Internal Korean Medicine
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• v.27 no.4
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• pp.864-878
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• 2006

Purpose : Panax ginseng(PG) is considered to have salutary effects and stimulant actions on physical capacity. However, the effects of PG on the inflammatory cytokine secretion and hypoxia condition are still not understood. This study wasto elucidate the effect of PG on inflammatory cytokine secretion such as interleukin (IL)-1, IL-6, granulocyte macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor $(TNF)-{\alpha}$. Also, the effects on the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1) were measured. Methods : The water extract of PG was administrated to HMC-1 cells before phorbol myristate acetate (PMA)+A23187 treatment. $IL-1{\beta}$, IL-6, $TNF-{\alpha}$, GM-CSF, and VEGF secretion were measured by a modified enzyme-linked immunosorbent assay (ELISA). HIF-1 activation was measured by transcription factor enzyme-linked immunoassay (TF-EIA) Results : PG significantly decreased secretion of $IL-1{\beta}$, IL-6, $TNF-{\alpha}$, and GM-CSF in PMA+A23187-induced HMC-1 cells. VEGF secretion was not changed but HIF-1 activation was decreased by the treatment of PG. Conclusions : PG inhibited the secretion of inflammatory cytokines, which impliesPG might contribute to treatment of mast cell-mediated inflammatory disease. Also, PG inhibited PMA+A23187-induced $HIF -1{\alpha}activation}$ and DNA-binding activity for HIF-1. Therefore, these data demonstrate that PG modulates inflammatory cytokines through inhibition of $HIF-1{\alpha}activation}$ activation.

• Korean Journal of Plant Resources
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• v.35 no.3
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• pp.391-398
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• 2022

Ulcerative colitis (UC) is a typical inflammatory colon disorder. Platycodon grandiflorum (PG) is known to exert various beneficial effects including anti-oxidative and anti-bacterial properties and improvements in liver function. However, the improving effect and mechanism of PG on intestinal inflammation are not fully understood. The present research was designed to investigate the effect of PG on the clinical signs of DSS-induced colitis in mice. The ameliorative effects of PG on inflammatory cytokine expression and the activation of hypoxia-inducible-factor (HIF)-1α in DSS-treated colon tissue were also determined. Our results showed that mice treated with DSS displayed the main clinical symptoms of colitis, including weight loss, bloody stools, decrease in colon length and diarrhea and PG treatment significantly improved the clinical features induced by DSS in mice. PG inhibited the increase in the levels of inflammatory cytokines caused by DSS in colon tissues. We also showed that the anti-inflammatory mechanism of PG involved suppressing the activation of HIF-1α in DSS-treated colon tissues. Collectively, the findings of this study indicate the prospect of developing new drugs from PG for UC treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.6
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• pp.3613-3618
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• 2013

Object: To detect expression of hypoxia inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) and lysyl oxidase (LOX) in non-small cell lung cancer (NSCLC) and explore their roles in prognosis. Methods: The mRNA levels of HIF-$1{\alpha}$ and LOX were investigated by real-time reverse-transcriptase polymerase chain reaction in 40 cases of tumour and paired normal tissues. In addition, protein expression of HIF-$1{\alpha}$ and LOX was examined by immunohistochemistry in 82 cases of tumour and 45 paired normal tissues. The relationship between HIF-$1{\alpha}$ or LOX and clinicopathologic characteristics, as well as the correlation between HIF-$1{\alpha}$ and LOX, were also examined. Kaplan-Meier survival curves and the log-rank test were used to analyze progression-free survival. Results: HIF-$1{\alpha}$ or LOX mRNA levels in tumor tissues was significantly higher than those in paired normal tissues (p<0.01). Positive HIF-$1{\alpha}$ or LOX protein expression in tumor tissues was noted in 46/82 (56.1%) and 49/82 (59.8%) of the cases, respectively, being significantly higher than those in paired normal tissues (p<0.05). There was significant correlation between the expression of HIF-$1{\alpha}$ or LOX and tumor size, lymph node metastasis and pathological stage (p<0.05). The expression of HIF-$1{\alpha}$ and LOX had a significant inverse impact on survival of patients with NSCLC. Conclusion: HIF-$1{\alpha}$ and LOX may play a pivotal role in the development of NSCLC, and may act in synergy to promote the progression of NSCLC.

• BMB Reports
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• v.49 no.9
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• pp.508-513
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• 2016

Hypoxia-inducible factor (HIF)-1α is a key regulator associated with tumorigenesis, angiogenesis, and metastasis. HIF-1α regulation under hypoxia has been highlighted as a promising therapeutic target in angiogenesis-related diseases. Here, we demonstrate that diacetyl atractylodiol (DAA) from Atractylodes japonica (A. japonica) is a potent HIF-1α inhibitor that inhibits the Akt signaling pathway. DAA dose-dependently inhibited hypoxia-induced HIF-1α and downregulated Akt signaling without affecting the stability of HIF-1α protein. Furthermore, DAA prevented hypoxia-mediated angiogenesis based on in vitro tube formation and in vivo chorioallantoic membrane (CAM) assays. Therefore, DAA might be useful for treatment of hypoxia-related tumorigenesis, including angiogenesis.

• BMB Reports
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• v.47 no.7
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• pp.411-416
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• 2014

In the present study, we demonstrate that ectopic expression of 56-kDa human selenium binding protein-1 (hSP56) in PC-3 cells that do not normally express hSP56 results in a marked inhibition of cell growth in vitro and in vivo. Down-regulation of hSP56 in LNCaP cells that normally express hSP56 results in enhanced anchorage-independent growth. PC-3 cells expressing hSP56 exhibit a significant reduction of hypoxia inducible protein (HIF)-$1{\alpha}$ protein levels under hypoxic conditions without altering HIF-$1{\alpha}$ mRNA (HIF1A) levels. Taken together, our findings strongly suggest that hSP56 plays a critical role in prostate cells by mechanisms including negative regulation of HIF-$1{\alpha}$, thus identifying hSP56 as a candidate anti-oncogene product.