Stabilization of RNT-1 Protein, Runt-related Transcription Factor (RUNX) Protein Homolog of Caenorhabditis elegans, by Oxidative Stress through Mitogen-activated Protein Kinase Pathway

Lee, Kiho; Shim, Jiwon; Bae, Jonghee; Kim, Young-Joon; Lee, Jun-Ho

doi:10.1074/jbc.m111.314146

Cited by 13 publications

(11 citation statements)

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“…NRF2 is also one of the top three TFs associated with Cluster 2, but this cluster is most enriched for RUNX1-bound genes. Interestingly, although RUNX1 has not previously been implicated with gene induction in response to ROS, RNT-1, a nematode ortholog of RUNX1, regulates oxidative stress responsive gene expression in Caenorhabditis elegans [35] ; this connection may indicate a previously unrecognized redox-responsive role for human RUNX1. Repressed gene sets are associated with TFs like the cell cycle regulator E2F4 (Clusters 6, 10, 14) [36] and hepatocyte specification factor HNF4A (Cluster 10) [37] , suggesting that prolonged ROS exposure represses both proliferation and hepatocyte identity regulatory networks.…”

Section: Resultsmentioning

confidence: 99%

Identification of a functional antioxidant response element at the HIF1A locus

et al. 2018

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Reactive oxygen species (ROS), which are a byproduct of oxidative metabolism, serve as signaling molecules in a number of physiological settings. However, if their levels are not tightly maintained, excess ROS lead to potentially cytotoxic oxidative stress. Accordingly, several transcriptional regulatory networks have evolved to include components that are highly ROS-responsive. Depending on the context, these regulatory networks can leverage ROS to respond to nutrient conditions, metabolism, or other physiological signals, or to respond to oxidative stress. However, ROS signaling is complex, so regulatory interactions between various ROS-responsive transcription factors are still being mapped out. Here we show that the transcription factor NRF2, a key regulator of the adaptive response to oxidative stress, directly regulates expression of HIF1A, which encodes HIF1α, a key transcriptional regulator of the adaptive response to hypoxia. We used an integrative genomics approach to identify HIF1A as a ROS-responsive transcript and we found an NRF2-bound antioxidant response element (ARE) approximately 30 kilobases upstream of HIF1A. This ARE sequence is deeply conserved, and we verified that it is directly bound and activated by NRF2. In addition, we found that HIF1A is upregulated in breast and bladder tumors with high NRF2 activity. Taken together, our results demonstrate that NRF2 targets a functional ARE at the HIF1A locus, and reveal a direct regulatory connection between two important oxygen responsive transcription factors.

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Section: Resultsmentioning

confidence: 99%

Identification of a functional antioxidant response element at the HIF1A locus

et al. 2018

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“…VHP-1 is a dual-specificity phosphatase that interacts with multiple MAP kinases including KGB-1, PMK-3, and PMK-1 [40-42] and plays a role in modulating the respective signaling pathways during response to stress. It has been shown to be regulated by RNT-1 during oxidative stress [41]. It is likely that the increased expression of vhp-1 and the concurrent repression of the PMK-1 pathway are the results of dichlorvos-induced stress.…”

Section: Resultsmentioning

confidence: 99%

Alterations in gene expression in Caenorhabditis elegans associated with organophosphate pesticide intoxication and recovery

et al. 2013

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BackgroundThe principal toxicity of acute organophosphate (OP) pesticide poisoning is the disruption of neurotransmission through inhibition of acetylcholinesterase (AChE). However, other mechanisms leading to persistent effects and neurodegeneration remain controversial and difficult to detect. Because Caenorhabditis elegans is relatively resistant to OP lethality—particularly through the inhibition of AChE—studies in this nematode provide an opportunity to observe alterations in global gene expression following OP exposure that cannot be readily observed in less resistant organisms.ResultsWe exposed cultures of worms in axenic, defined medium to dichlorvos under three exposure protocols. In the first, worms were exposed continuously throughout the experiment. In the second and third, the worms were exposed for either 2 or 8 h, the dichlorvos was washed out of the culture, and the worms were allowed to recover. We then analyzed gene expression using whole genome microarrays from RNA obtained from worms sampled at multiple time points throughout the exposure. The worms showed a time-dependent increase in the expression of genes involved in stress responses. Early in the exposure, the predominant effect was on metabolic processes, while at later times, an immune-like response and cellular repair mechanisms dominated the expression pattern. Following removal of dichlorvos, the gene expression in the worms appeared to relatively rapidly return to steady-state levels.ConclusionThe changes in gene expression observed in the worms following exposure to dichlorvos point towards two potential mechanisms of toxicity: inhibition of AChE and mitochondrial disruption.

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“…Following adriamycin insult, RUNX3 binds to p53 and enhances p53‐mediated transcription activation, and RUNX3 can also associate with phosphorylated ATM 94. It is extremely significant that the RUNX homolog in C. elegans RNT‐1 is stabilized in the intestines in response to oxidative stress via the p38 mitogen‐activated protein kinase (MAP) pathway 95. This suggests an evolutionarily conserved role for RUNX proteins in stress response.…”

Section: Runx In Cancermentioning

confidence: 99%

RUNX family: Regulation and diversification of roles through interacting proteins

Chuang

Ito

2012

Intl Journal of Cancer

156

161

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The Runt-related transcription factors (RUNX) belong to an ancient family of metazoan genes involved in developmental processes. Through multiple protein-interacting partners, RUNX proteins have been implicated in diverse signaling pathways and cellular processes. The frequent inactivation of RUNX genes in cancer indicates crucial roles for RUNX in tumor suppression. This review discusses the abilities of RUNX proteins, in particular RUNX3, to integrate oncogenic signals or environmental cues and to initiate appropriate tumor suppressive responses.RUNX proteins are crucial transcription factors that regulate a wide range of biological processes to orchestrate proper cell fate determination. Traditionally described as a DNA-binding protein that binds CBFb (also known as PEBP2b) to form the heterodimeric core-binding factor (CBF) or polyomavirus enhancer-binding protein 2 (PEBP2) transcription complex, RUNX is now viewed as a multifaceted protein that associates with diverse proteins to direct biological outcomes in a context-dependent manner. 1 This review discusses how combinatorial interactions-dynamically regulated in a spatiotemporal manner-have endowed RUNX proteins with a plethora of functions, some seemingly opposite. Because of space constraints, emphasis will be placed on the tumor suppressive properties of RUNX3.RUNX proteins have been identified in many metazoans: most, if not all, play requisite roles in developmental processes. While primitive metazoans such as sea urchin and C. elegans appear to possess a single RUNX family member, multiple RUNX proteins have been identified in mammals, Drosophila and Fugu, 2 indicating (i) evolutionary conserved roles in metazoans and (ii) the necessity for elaborate and tight regulation of RUNX activity when specifying complex developmental events in higher organisms. In mammals, there are three RUNX family members: RUNX1, RUNX2 and RUNX3. Mouse models have shown that disruption of individual Runx genes resulted in distinct phenotypes, indicating nonredundant, tissue-specific roles: Runx1 knockout is associated with lack of definitive hematopoiesis; Runx2 knockout resulted in the absence of bone formation and Runx3 knockout led to mice with defects in cytotoxic T-cell development, as well as gastrointestinal (GI) and neural disorders. 3-5 During T-lymphocyte development, Runx3 involvement in the establishment of epigenetic silencing of CD4 is critical for lineage specification and homeostasis, and the absence of Runx3 is associated with defective cytotoxic T cells 6 ; in the intestine, heterozygous inactivation of Runx3 induced colon adenoma; in the gastric epithelia, Runx3 deficiency is associated with a precancerous state, distinctly characterized by loss of chief cells 7 and in the lung, Runx3 plays requisite roles during bronchiolar epithelial cell differentiation and tumor suppression. 8,9 All offer compelling evidence for a causal link between loss of Runx3, deregulated differentiation and preneoplasia. Together with the fact that Runx3-deficient mice are tu...

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Stabilization of RNT-1 Protein, Runt-related Transcription Factor (RUNX) Protein Homolog of Caenorhabditis elegans, by Oxidative Stress through Mitogen-activated Protein Kinase Pathway

Cited by 13 publications

References 49 publications

Identification of a functional antioxidant response element at the HIF1A locus

Identification of a functional antioxidant response element at the HIF1A locus

Alterations in gene expression in Caenorhabditis elegans associated with organophosphate pesticide intoxication and recovery

RUNX family: Regulation and diversification of roles through interacting proteins

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