Nkx3.2 induces oxygen concentration-independent and lysosome-dependent degradation of HIF-1α to modulate hypoxic responses in chondrocytes

Im, Suhjean; Kim, Dae Won

doi:10.1016/j.cellsig.2017.05.001

Cited by 12 publications

(12 citation statements)

References 69 publications

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“…The HIF-1a controlled by oxygen was an ingredient that took part in the process of transcription and controlled the level of all kinds of genes [28], which were involved in cell growth and apoptosis, like CyclinD1, p62, Bax and Bcl-2. In our studies, H 2 O 2 increased HIF-1a level in PC12 cells and Dex further promoted the increase of HIF-1a level, thereby protected cells from oxidative damage.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine protects PC12 cells from oxidative damage through regulation of miR-199a/HIF-1α

Yang

Kong

2020

Artificial Cells, Nanomedicine, and Biotechnology

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Background: Although dexmedetomidine (Dex) has a significant neuroprotective effect in various nerve-damage models, the exact mechanism of which Dex protects cells from oxidative damage is not fully clear. This article recommended the protective effect of Dex on oxidative damage in PC12 cells. Methods: The PC12 cells were incubated by hydrogen peroxide (H 2 O 2) for 24 h and pre-treated by Dex for 30 min. Cell viability, apoptosis, HIF-1a expression and ROS level were detected by CCK-8, apoptosis assay, Western blot and ROS assay, respectively. The miR-199a expression was tested by qRT-PCR. Targeting relationship between miR-199a and HIF-1a was performed by dual luciferase activity assay. The activation of PI3K/AKT/mTOR and Wnt/b-catenin pathways was tested by western blot. Results: Dex attenuated H 2 O 2-induced oxidative damage, including the decline of cell viability, the raise of apoptosis and the generation of ROS in PC12 cells by down-regulating miR-199a expression. Moreover, Dex up-regulated HIF-1a expression via decreasing miR-199a level in PC12 cells and miR-199a targeted the 3 0-UTR of HIF-1a. In addition, Dex activated PI3K/AKT/mTOR and Wnt/b-catenin pathways by declining miR-199a level. Conclusions: This article illustrated the protective effect of Dex on oxidative damage in PC12 cells. Furthermore, Dex prevented PC12 cells from oxidative injury through the regulation of miR-199a/ HIF-1a.

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Section: Discussionmentioning

confidence: 99%

Dexmedetomidine protects PC12 cells from oxidative damage through regulation of miR-199a/HIF-1α

Yang

Kong

2020

Artificial Cells, Nanomedicine, and Biotechnology

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“…Upon proline hydroxylation, HIF-1α is ubiquitinated and subsequent degraded in proteasomes by the von Hippel-Lindau (VHL) ubiquitin ligase complex in an oxygen-dependent manner 95,96, whereas in both normoxic and hypoxic conditions, CMA components HSC70 and LAMP2A interact with HIF-1α and promote the recruitment of an E3 ubiquitin ligase STUB1/CHIP for lysosomal translocation and degradation 97-99. Additionally, selective macroautophagy has been demonstrated to degrade HIF-1α via p62-mediated recognition and binding to the STUB1-HIF-1α complex, which can be further enhanced by chondrogenic factor Nkx3.2 100. Furthermore, p62 can interact directly with the VHL E3 ligase complex and block the VHL-mediated ubiquitylation and proteasomal degradation of HIF-1α 101, indicating an alternative crosstalk that switches HIF-1α degradation between these two systems.…”

Section: Selective Autophagy Regulates Cell Cyclementioning

confidence: 99%

Selective Autophagy Regulates Cell Cycle in Cancer Therapy

et al. 2019

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Aberrant function of cell cycle regulators results in uncontrolled cell proliferation, making them attractive therapeutic targets in cancer treatment. Indeed, survival of many cancers exclusively relies on these proteins, and several specific inhibitors are in clinical use. Although the ubiquitin-proteasome system is responsible for the periodic quality control of cell cycle proteins during cell cycle progression, increasing evidence clearly demonstrates the intimate interaction between cell cycle regulation and selective autophagy, important homeostasis maintenance machinery. However, these studies have often led to divergent rather than unifying explanations due to complexity of the autophagy signaling network, the inconsistent functions between general autophagy and selective autophagy, and the different characteristics of autophagic substrates. In this review, we highlight current data illustrating the contradictory and important role of cell cycle proteins in regulating autophagy. We also focus on how selective autophagy acts as a central mechanism to maintain orderly DNA repair and genome integrity by degrading specific cell cycle proteins, regulating cell division, and promoting DNA damage repair. We further discuss the ways in which selective autophagy may impact the cell cycle regulators, since failure to appropriately remove these can interfere with cell death-related processes, including senescence and autophagy-related cell death. Imbalanced cell proliferation is typically utilized by cancer cells to acquire resistance. Finally, we discuss the possibility of a potent anticancer therapeutic strategy that targets selective autophagy or autophagy and cell cycle together.

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“…To this end, the most highly enriched transcription factor motifs for promoter- and enhancer-associated lncRNAs were clearly distinct. Regions near eRNAs exhibited strongest enrichments for AP-1/Jun and NKX3, factors previously implicated in the control of vascularization ( 53 , 54 ), and MAFA, a known regulator of energy homeostasis that can act both as activator and repressor of transcription ( 55 ). In line with their genomic origin, p-lncRNAs revealed enrichment for motifs known to be promoter-proximal, such as binding motifs for Sp1 and NRF1 ( 56 , 57 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of Hypoxia-Regulated Non-coding RNAs in Human Primary Endothelial Cells

Moreau

Örd

Downes

et al. 2018

Front. Cardiovasc. Med.

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Hypoxia occurs in human atherosclerotic lesions and has multiple adverse effects on endothelial cell metabolism. Recently, key roles of long non-coding RNAs (lncRNAs) in the development of atherosclerosis have begun to emerge. In this study, we investigate the lncRNA profiles of human umbilical vein endothelial cells subjected to hypoxia using global run-on sequencing (GRO-Seq). We demonstrate that hypoxia regulates the nascent transcription of ~1800 lncRNAs. Interestingly, we uncover evidence that promoter-associated lncRNAs are more likely to be induced by hypoxia compared to enhancer-associated lncRNAs, which exhibit an equal distribution of up- and downregulated transcripts. We also demonstrate that hypoxia leads to a significant induction in the activity of super-enhancers next to transcription factors and other genes implicated in angiogenesis, cell survival and adhesion, whereas super-enhancers near several negative regulators of angiogenesis were repressed. Despite the majority of lncRNAs exhibiting low detection in RNA-Seq, a subset of lncRNAs were expressed at comparable levels to mRNAs. Among these, MALAT1, HYMAI, LOC730101, KIAA1656, and LOC339803 were found differentially expressed in human atherosclerotic lesions, compared to normal vascular tissue, and may thus serve as potential biomarkers for lesion hypoxia.

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Nkx3.2 induces oxygen concentration-independent and lysosome-dependent degradation of HIF-1α to modulate hypoxic responses in chondrocytes

Cited by 12 publications

References 69 publications

Dexmedetomidine protects PC12 cells from oxidative damage through regulation of miR-199a/HIF-1α

Dexmedetomidine protects PC12 cells from oxidative damage through regulation of miR-199a/HIF-1α

Selective Autophagy Regulates Cell Cycle in Cancer Therapy

Transcriptional Profiling of Hypoxia-Regulated Non-coding RNAs in Human Primary Endothelial Cells

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