Regulation of Hypoxia-inducible Factor 1α (HIF-1α) by Lysophosphatidic Acid Is Dependent on Interplay between p53 and Krüppel-like Factor 5

Lee, Sei-Jung; No, Yi Ran; Dang, Duyen T.; Dang, Long H.; Yang, Vincent W.; Shim, Hyunsuk; Yun, C. Chris

doi:10.1074/jbc.m113.489708

Cited by 60 publications

(59 citation statements)

References 55 publications

(42 reference statements)

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“…20 Unsaturated LPAs are produced during mild oxidation of LDL and induce the upregulation of Hif1a expression by activating LPA receptors in cancer cells and in smooth muscle cells. 21,22 In line with these reports, our findings indicate that hyperlipidemia-induced endothelial HIF-1α activation is because of LPA receptor signaling triggered by moxLDL-derived LPAs. 6 In addition, LPAs activate proatherogenic NF-κB signaling in ECs.…”

Section: Discussionsupporting

confidence: 80%

Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a

et al. 2015

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Chemokines mediate monocyte adhesion to dysfunctional endothelial cells (ECs) and promote arterial inflammation during atherosclerosis. Hypoxia-inducible factor (HIF)-1α is expressed in various cell types of atherosclerotic lesions and is associated with lesional inflammation. However, the impact of endothelial HIF-1α in atherosclerosis is unclear. HIF-1α was detectable in the nucleus of ECs covering murine and human atherosclerotic lesions. To study the role of endothelial HIF-1α in atherosclerosis, deletion of the Hif1 a gene was induced in ECs from apolipoprotein E knockout mice (EC- Hif1a −/− ) by Tamoxifen injection. The formation of atherosclerotic lesions, the lesional macrophage accumulation, and the expression of CXCL1 in ECs were reduced after partial carotid ligation in EC- Hif1a −/− compared with control mice. Moreover, the lesion area and the lesional macrophage accumulation were decreased in the aortas of EC- Hif1a −/− mice compared with control mice during diet-induced atherosclerosis. In vitro, mildly oxidized low-density lipoprotein or lysophosphatidic acid 20:4 increased endothelial CXCL1 expression and monocyte adhesion by inducing HIF-1α expression. Moreover, endothelial Hif1a deficiency resulted in downregulation of miR-19a in atherosclerotic arteries determined by microRNA profiling. In vitro, HIF-1α–induced miR-19a expression mediated the upregulation of CXCL1 in mildly oxidized low-density lipoprotein–stimulated ECs. These results indicate that hyperlipidemia upregulates HIF-1α expression in ECs by mildly oxidized low-density lipoprotein–derived unsaturated lysophosphatidic acid. Endothelial HIF-1α promoted atherosclerosis by triggering miR-19a–mediated CXCL1 expression and monocyte adhesion, indicating that inhibition of the endothelial HIF-1α/miR-19a pathway may be a therapeutic option against atherosclerosis.

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Section: Discussionsupporting

confidence: 80%

Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a

et al. 2015

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“…Moreover, the adrenoreceptors have been shown to functionally interact with opioid receptors (43), which elicit protective actions in response to pre-and post-conditioning stimuli upon cardiac and cerebral damages (44,45). It is worth noting that certain ligand-activated GPCRs induce HIF-1 expression and function (46)(47)(48), thus mimicking hypoxic conditions. For instance, the recruitment of transcription factors to the promoter sequence of HIF-1 as well as the stabilization of HIF-1 protein levels may occur upon activation of GPCRs by endothelin-1 (ET-1), β-adrenoceptor agonists, and lysophosphatidic acid (46)(47)(48).…”

Section: Gpcr Involvement In Hypoxia-mediated Signalingmentioning

confidence: 99%

“…It is worth noting that certain ligand-activated GPCRs induce HIF-1 expression and function (46)(47)(48), thus mimicking hypoxic conditions. For instance, the recruitment of transcription factors to the promoter sequence of HIF-1 as well as the stabilization of HIF-1 protein levels may occur upon activation of GPCRs by endothelin-1 (ET-1), β-adrenoceptor agonists, and lysophosphatidic acid (46)(47)(48).…”

Section: Gpcr Involvement In Hypoxia-mediated Signalingmentioning

confidence: 99%

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

Lappano

Rigiracciolo

Marco

et al. 2016

AAPS J

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Abstract. G protein-coupled receptors (GPCRs) are cell surface proteins mainly involved in signal transmission; however, they play a role also in several pathophysiological conditions. Chemically heterogeneous molecules like peptides, hormones, lipids, and neurotransmitters activate second messengers and induce several biological responses by binding to these seven transmembrane receptors, which are coupled to heterotrimeric G proteins. Recently, additional molecular mechanisms have been involved in GPCR-mediated signaling, leading to an intricate network of transduction pathways. In this regard, it should be mentioned that diverse GPCR family members contribute to the adaptive cell responses to low oxygen tension, which is a distinguishing feature of several illnesses like neoplastic and cardiovascular diseases. For instance, the G protein estrogen receptor, namely G protein estrogen receptor (GPER)/GPR30, has been shown to contribute to relevant biological effects induced by hypoxia via the hypoxia-inducible factor (HIF)-1α in diverse cell contexts, including cancer. Likewise, GPER has been found to modulate the biological outcome of hypoxic/ischemic stress in both cardiovascular and central nervous systems. Here, we describe the role exerted by GPCR-mediated signaling in low oxygen conditions, discussing, in particular, the involvement of GPER by a hypoxic microenvironment.

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“…In a recent research about colon cancer, the authors suggested that LPA induced proliferation of colon cancer cells through upregulation of HIF1α by dynamically modulating its interaction with KLF5 and P53. 70 Another research about colon cancer found that LPA stimulated proliferation of colon cancer cells by activation of β-catenin through multiple pathways involving phosphorylation of GSK-3 and β-catenin, and enhancing β-catenin interaction with TCF4, which could be enhanced by KLF5 via increasing the β-catenin-TCF4 interaction. 71 ATX has been reported to act as a motility and growth factor in a variety of cancer cells, and has important functions in cell migration and proliferation.…”

Section: Expression Of Atx/lpa Axis In Cancermentioning

confidence: 99%

The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

et al. 2017

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Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1-6). This review provides an overview of the autotaxin/lysophosphatidate axis and collates current knowledge regarding its specific role in pancreatic cancer. With a deeper understanding of the critical role of the autotaxin/lysophosphatidate axis in pancreatic cancer, targeting autotaxin or lysophosphatidate receptor may be a potential and promising strategy for cancer therapy.

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Regulation of Hypoxia-inducible Factor 1α (HIF-1α) by Lysophosphatidic Acid Is Dependent on Interplay between p53 and Krüppel-like Factor 5

Cited by 60 publications

References 55 publications

Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a

Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

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