ChemInform Abstract: Diaryl-Substituted Carboranes as Inhibitors of Hypoxia Inducible Factor-1 Transcriptional Activity

ChemInform ◽  
2015 ◽  
Vol 46 (24) ◽  
pp. no-no
Author(s):  
Hiroyuki Nakamura ◽  
Lisa Tazaki ◽  
Daisuke Kanoh ◽  
Shinichi Sato
Keyword(s):  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1

Nitric oxide modulates hypoxia-inducible factor-1 and poly(ADP-ribose) polymerase-1 cross talk in response to hypobaric hypoxia

2012 ◽  
Vol 112 (5) ◽  
pp. 816-823 ◽  
Author(s):  
Rubén Martínez-Romero ◽  
Ana Cañuelo ◽  
Eva Siles ◽  
F. Javier Oliver ◽  
Esther Martínez-Lara
Keyword(s):  
Nitric Oxide ◽  
Hypobaric Hypoxia ◽  
Reactive Oxygen Species Production ◽  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
No Production ◽  
Oxygen Species ◽  
Hypoxia Inducible Factor 1 ◽  
Species Production ◽  
Parp 1

The physiological response to hypobaric hypoxia represents a complex network of biochemical pathways in which the nitrergic system plays an important role. Previous studies have provided evidence for an interplay between the hypoxia-inducible factor-1 (HIF-1) and poly(ADP-ribose) polymerase-1 (PARP-1) under hypoxia. Here, we evaluate the potential involvement of nitric oxide (NO) in the cross talk between these two proteins. With this aim, we studied comparatively the effect of pharmacological inhibitors of NO production or PARP activity in the response of the mouse cerebral cortex to 4 h of exposure to a simulated altitude of 31,000 ft. Particularly, we analyzed the NO and reactive oxygen species production, the expression of NO synthase (NOS) isoforms, PARP-1 activity, HIF-1α expression and HIF-1 transcriptional activity, the protein level of the factor inhibiting HIF, and, finally, beclin-1 and fractin expression, as markers of cellular damage. Our results demonstrate that the reduction of NO level did not affect reactive oxygen species production but significantly 1) dampened the posthypoxic increase in neuronal NOS and inducible NOS expression without altering endothelial NOS protein level; 2) prevented PARP activation; 3) decreased HIF-1α response to hypoxia; 4) achieved a higher long-term HIF-1 transcriptional activity by reducing factor inhibiting HIF expression; and 5) reduced hypoxic damage. The pharmacological inhibition of PARP reproduced the NOS expression pattern and the HIF-1α response observed in NOS-inhibited mice, supporting its involvement in the NO-dependent regulation of hypoxia. As a whole, these results provide new data about the molecular mechanism underlying the beneficial effects of controlling NO production under hypobaric hypoxic conditions.

scholarly journals Virus-based reporter systems for monitoring transcriptional activity of hypoxia-inducible factor 1

Gene ◽  
2005 ◽  
Vol 350 (1) ◽  
pp. 89-98 ◽  
Author(s):  
O.V. Razorenova ◽  
A.V. Ivanov ◽  
A.V. Budanov ◽  
P.M. Chumakov
Keyword(s):  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Reporter Systems

scholarly journals HIF-1: the knowns and unknowns of hypoxia sensing.

2004 ◽  
Vol 51 (3) ◽  
pp. 563-585 ◽  
Author(s):  
Anna Zagórska ◽  
Józef Dulak
Keyword(s):  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Oxygen Homeostasis ◽  
Wide Range ◽  
Systemic Oxygen ◽  
Prolyl Hydroxylation ◽  
Energy Deprivation ◽  
Direct Inhibitors

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator that functions as a master regulator of cellular and systemic oxygen homeostasis. It consists of two constitutively produced subunits: HIF-1alpha and HIF-1beta. Under normoxic conditions HIF-1alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the alpha subunit. Additionally, hydroxylation of an asparaginyl residue blocks the transcriptional activity of HIF-1 due to inhibition of its interaction with co-activators. In contrast, under hypoxic conditions, abolition of prolyl hydroxylation results in HIF-1alpha stabilization, whereas the lack of asparaginyl hydroxylation allows the transcriptional activity. Additionally, the transcriptional activity may be modulated by phosphorylation or redox modification of HIF-1. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, various growth factors, or direct inhibitors of prolyl and asparaginyl hydroxylases. Therefore, it seems to be a crucial transcription factor elicited by a wide range of stresses such as impaired oxygenation, inflammation, energy deprivation, or intensive proliferation. However, the mechanisms of normoxic activation, as well as of oxygen sensing, are not yet fully known. Further understanding of the processes that control HIF-1 activity will be crucial for the development of new diagnostic and therapeutic strategies.

scholarly journals Protein kinase A–dependent phosphorylation stimulates the transcriptional activity of hypoxia-inducible factor 1

2016 ◽  
Vol 9 (430) ◽  
pp. ra56-ra56 ◽  
Author(s):  
John W. Bullen ◽  
Irina Tchernyshyov ◽  
Ronald J. Holewinski ◽  
Lauren DeVine ◽  
Fan Wu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Kinase A

Sirtuin-1 inhibits endothelin-2 expression in human granulosa-lutein cells via hypoxia inducible factor 1 alpha and epigenetic modifications†

2020 ◽  
Author(s):  
Magdalena Szymanska ◽  
Sarah Manthe ◽  
Ketan Shrestha ◽  
Eliezer Girsh ◽  
Avi Harlev ◽  
...  
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Sirtuin 1 ◽  
Class Iii ◽  
Inhibitory Interaction ◽  
Hypoxia Inducible Factor 1 ◽  
Promote Cell Survival ◽  
Chip Analysis ◽  
Sirt1 Activator

Abstract Endothelin-2 (EDN2) expression in granulosa cells was previously shown to be highly dependent on the hypoxic mediator, hypoxia inducible factor 1 alpha (HIF1A). Here, we investigated whether sirtuin-1 (SIRT1), by deacetylating HIF1A and class III histones, modulates EDN2 in human granulosa-lutein cells (hGLCs). We found that HIF1A was markedly suppressed in the presence of resveratrol or a specific SIRT1 activator, SRT2104. In turn, hypoxia reduced SIRT1 levels, implying a mutually inhibitory interaction between hypoxia (HIF1A) and SIRT1. Consistent with reduced HIF1A transcriptional activity, SIRT1 activators, resveratrol, SRT2104, and metformin, each acting via different mechanisms, significantly inhibited EDN2. In support, knockdown of SIRT1 with siRNA markedly elevated EDN2, whereas adding SRT2104 to SIRT1-silenced cells abolished the stimulatory effect of siSIRT1 on EDN2 levels further demonstrating that EDN2 is negatively correlated with SIRT1. Next, we investigated whether SIRT1 can also mediate the repression of the EDN2 promoter via histone modification. Chromatin immunoprecipitation (ChIP) analysis revealed that SIRT1 is indeed bound to the EDN2 promoter and that elevated SIRT1 induced a 40% decrease in the acetylation of histone H3, suggesting that SIRT1 inhibits EDN2 promoter activity by inducing a repressive histone configuration. Importantly, SIRT1 activation, using SRT2104 or resveratrol, decreased the viable numbers of hGLC, and silencing SIRT1 enhanced hGLC viability. This effect may be mediated by reducing HIF1A and EDN2 levels, shown to promote cell survival. Taken together, these findings propose novel, physiologically relevant roles for SIRT1 in downregulating EDN2 and survival of hGLCs.

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