HIF-1α is required for development of the sympathetic nervous system

Bohuslavová, Romana; Čerychová, Radka; Papoušek, F; Olejníčková, Veronika; Bartoš, Martin; Görlach, Agnes; Kolář, František; Sedmera, David; Semenza, Gregg L.; Pavlínková, Gabriela

doi:10.1073/pnas.1903510116

Cited by 55 publications

(56 citation statements)

References 68 publications

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“…Chronic hypoxia treatment of wild-type mice leads to the development of polycythemia, right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling, all of which are delayed by partial HIF-1α deficiency in HIF1a +/− mice (117). Conditional and tissue-specific manipulation of VHL/HIF-1α pathway reveals pivotal roles in osteogenesis (118), pancreatic beta-cell insulin secretion (119), myeloid cell-mediated inflammation (120), and development of the sympathetic nervous system (121). A significant threat to cardiovascular health is cardiac ischemia and subsequent hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

HIF-transcribed p53 chaperones HIF-1α

Madan

Parker

Pelham

et al. 2019

Nucleic Acids Research

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Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.

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Section: Discussionmentioning

confidence: 99%

HIF-transcribed p53 chaperones HIF-1α

Madan

Parker

Pelham

et al. 2019

Nucleic Acids Research

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“…The expression of neuron-specific class III ß-tubulin (TuJ1), a neural differentiation marker, gets enriched in absence of transcription factor HIF1α, as reported in neural stem cell and mouse model (Bohuslavova et al, 2019;Vecera et al, 2018). Here in our study we have observed a loss of Tuj1 expression in both acute hypoxia groups (AHM and AHF) as compared to the corresponding normoxia groups, which confers with the onset of hypoxia in AH groups Hif 1 α expression is more as reported earlier (Das et al, 2019) which resulted in loss of Tuj1 expression, irrespective of sex.…”

Section: Discussionmentioning

confidence: 82%

Molecular Basis of Sex Difference in Neuroprotection induced by Hypoxia Preconditioning in Zebrafish

Das¹,

Soren²,

Yerasi³

et al. 2020

Preprint

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Hypoxia, the major cause of ischemia, leads to debilitating disease in infants via birth asphyxia and cerebral palsy, whereas in adults via heart attack and stroke. A widespread, natural protective phenomenon termed 'Hypoxic Preconditioning' occurs when prior exposures to hypoxia eventually results in robust hypoxia resistance. Accordingly, we have developed a novel model of sex-specific hypoxic preconditioning in adult zebrafish to mimic the tolerance of mini stroke(s) in human, which appears to protect against the severe damage inflicted by a major stroke event. Remarkable difference in the progression pattern of neuroprotection between preconditioning hypoxia followed by acute hypoxia (PH) group, and acute hypoxia (AH) group were observed with noticeable sex difference. Since gender difference has been reported in stroke, it was pertinent to investigate whether any such sex difference also exists in PH's protective mechanism against acute ischemic stroke. In order to elucidate the neural molecular mechanisms behind sex difference in neuroprotection induced by PH, a high throughput proteomics approach utilizing iTRAQ was performed, followed by protein enrichment analysis

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“…Interestingly, hypoxia, a microenvironmental condition that promotes tumor progression and immune evasion, also modulates Cx43 expression and function in cancer and other biological contexts. Interestingly, recent data shows a significantly decrease in Cx43 expression in the left ventricular of HIF-1α conditional knockout mice, which may contribute to impaired heart contractility [ 54 ]. This HIF-1α-dependent Cx43 expression in cardiac cells supports our previous evidence showing that HIF-1α binds GJA1 promoter, inducing Cx43 expression in hypoxic melanoma cells [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels

Tittarelli

Navarrete

Lizana

et al. 2020

IJMS

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Alterations in microRNA (miRNA) profiles, induced by tumor microenvironment stressors, like hypoxia, allow cancer cells to acquire immune-resistance phenotypes. Indeed, hypoxia-induced miRNAs have been implicated in cancer progression through numerous cancer cell non-autonomous mechanisms, including the direct transfer of hypoxia-responsive miRNA from cancer to immune cells via extracellular vesicles. Connexin-43 (Cx43)-constituted gap junctions (GJs) have also been involved in miRNA intercellular mobilization, in other biological processes. In this report, we aimed to evaluate the involvement of Cx43-GJs in the shift of miRNAs induced by hypoxia, from hypoxic melanoma cells to dendritic cells and melanoma-specific cytotoxic T lymphocytes (CTLs). Using qRT-PCR arrays, we identified that miR-192-5p was strongly induced in hypoxic melanoma cells. Immune cells acquired this miRNA after co-culture with hypoxic melanoma cells. The transfer of miR-192-5p was inhibited when hypoxic melanoma cells expressed a dominant negative Cx43 mutant or when Cx43 expression was silenced using specific short-hairpin RNAs. Interestingly, miR-192-5p levels on CTLs after co-culture with hypoxic melanoma cells were inversely correlated with the cytotoxic activity of T cells and with ZEB2 mRNA expression, a validated immune-related target of miR-192-5p, which is also observed in vivo. Altogether, our data suggest that hypoxic melanoma cells may suppress CTLs cytotoxic activity by transferring hypoxia-induced miR-192-5p through a Cx43-GJs driven mechanism, constituting a resistance strategy for immunological tumor escape.

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HIF-1α is required for development of the sympathetic nervous system

Cited by 55 publications

References 68 publications

HIF-transcribed p53 chaperones HIF-1α

HIF-transcribed p53 chaperones HIF-1α

Molecular Basis of Sex Difference in Neuroprotection induced by Hypoxia Preconditioning in Zebrafish

Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels

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