Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes

Mishra, Snigdha; Fujita, Tomoyuki; Lama, Vibha N.; Nam, Douglas; Liao, Hui; Okada, Morihito; Minamoto, Kanji; Yoshikawa, Yasushi; Harada, Hiroaki; Pinsky, David J.

doi:10.1073/pnas.0600241103

Cited by 91 publications

(94 citation statements)

References 35 publications

(45 reference statements)

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“…It has been reported that ERK 1/2 also regulates the activation of EGR-1. 33 Here we found that EGR-1 could also provide positive feedback to regulate Ras activation through its target gene GGPPS under CSE . The cells were then lysed and separated into membrane (P100) and cytosolic (S100) portions and subjected to immunoprecipitation and Western blotting against K-Ras and glyceraldehydes-3-phosphate dehydrogenase (GADPH), which was used to show that the separation of membrane and cytosol was successful.…”

Section: Discussionmentioning

confidence: 67%

“…[33][34][35][36][37][38] We have suggested that EGR-1 can also stimulate HSP70 elevation in an ERK 1/2-dependent manner, which is thought to regulate cigarette smoke-induced inflammatory processes. 18 Here we provide the first evidence that EGR-1 could activate MAPK ERK 1/2 in a positive feedback manner through increasing Ras prenylation by promoting GGPPS transcription in lung epithelial cells during CSE challenge (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

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GGPPS, a New EGR-1 Target Gene, Reactivates ERK 1/2 Signaling through Increasing Ras Prenylation

Shen

Shao

Lai

et al. 2011

The American Journal of Pathology

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Cigarette smoke activates the extracellular signal-regulated kinase (ERK) 1/2 mitogen activated-protein kinase pathway, which, in turn, is responsible for early growth response gene-1 (EGR-1) activation. Here we provide evidence that EGR-1 activation can also reactivate ERK 1/2 mitogen activated-protein kinase through a positive feedback loop through its target gene (geranylgeranyl diphosphate synthase) GGPPS. For the first time, the GGPPS gene is identified as a target of EGR-1, as EGR-1 can directly bind to the predicted consensus-binding site in the GGPPS promoter and regulate its transcription. Long-term observations show that there are two ERK 1/2 phosphorylation peaks after cigarette smoke extract stimulation in human lung epithelial Beas-2B cells. The first peak (at 10 minutes) is responsible for EGR-1 accumulation, and the second (at 4 hours) is diminished after the disruption of EGR-1 transcriptional activity. EGR-1 overexpression enhances Ras prenylation and membrane association in a GGPPS-dependent manner, and it augments ERK 1/2 activation. Likewise, a great reduction of the second peak of ERK 1/2 phosphorylation is observed during long-term cigarette smoke extract stimulation in cells where GGPPS is disrupted. Thus, we have uncovered an intricate positive feedback loop in which ERK 1/2-activated EGR-1 promotes ERK 1/2 reactivation through promoting GGPPS transcription, which might affect cigarette smoke-related lung pathological processes.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

GGPPS, a New EGR-1 Target Gene, Reactivates ERK 1/2 Signaling through Increasing Ras Prenylation

Shen

Shao

Lai

et al. 2011

The American Journal of Pathology

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“…; it has also been reported that carbon monoxide (CO) suppresses the pathogenesis of experimental cerebral malaria 45 . While pleiotropic mechanisms may explain the action of these gazes 45 47 48, it is documented that NO negatively modulates endothelium activation and platelet function 52 whereas CO inhibits the expression of pro-inflammatory genes (e.g., TF and TNF-α) and prevents inflammatory events in vivo 53 . Finally, the finding that TF is potentially a crucial mediator of malaria pathogenesis suggests that therapeutics targeting TF and/or EC 54 could be useful in the treatment of malaria and/or its complications 4,55 .…”

Section: Discussionmentioning

confidence: 99%

Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

Francischetti

2008

Trends in Parasitology

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Plasmodium falciparum infection is often associated with a procoagulant state. Recent identification of tissue factor (TF) in the brain endothelium of patients who died from cerebral malaria casts new light in our understanding of the coagulation disorder found in P. falciparum infection. It has also been revealed that parasitized red blood cells (pRBC) support assembly of multimolecular coagulation complexes. In this article, the role of TF expression by the endothelium and amplification of the coagulation cascade by pRBC and/or activated platelets-particularly at sequestration sitesis discussed as crucial events in mounting and sustaining a coagulation-inflammation cycle that contributes to organ dysfunction and coma in P. falciparum malaria. Blood coagulation and malariaMalaria caused by P. falciparum remains a highly endemic disease; it has been estimated that at least one million deaths occur every year. Children are at high risk, and often severe malaria (severe anemia or cerebral malaria [CM]) is the cause of death in this population 1-4. P. falciparum infection is associated with sequestration 5 -8 , endothelial cell (EC) activation 8-10, increase in inflammatory cytokines 3 , 11, and activation of the coagulation cascade 12 -20. Despite several papers devoted to the coagulation disorder in malaria-many of them published during the 1970s and 1980s (reviewed in Ref. 20)-the mechanism that triggers and propagates the coagulation activation in P. falciparum infection has remained elusive. These studies, however, demonstrated that bleeding and/or hemorrhage are typically not present, although laboratory tests indicate a certain degree of in vivo blood coagulation activation 12 -20 . Accordingly, prothrombin time (PT) and partial thromboplastin time (PTT) are close to normal values or prolonged, whereas thrombin-antithrombin complex (TAT) (which indicates in vivo thrombin formation) and D-dimers (which are a marker of in vivo fibrinolysis) are often elevated, and thrombocytopenia is a usual finding 12 -21 . This laboratory profile is compatible with disseminated intravascular coagulation (DIC), which is diagnosed according to a score defined by the International Society of Thrombosis and Haemostasis (ISTH) 22 . The scoring system takes into account i) platelet count, ii) elevated fibrin related markers, iii) prolonged prothrombin time, and iv) fibrinogen level 22 23 . Depending on the score punctuation, levels < 5 are suggestive of non-overt (compensated) DIC while scores > or = 5 are compatible with overt (decompensated) DIC. Bleeding is more common in overt DIC, but it is not needed for the formal diagnosis 22 23. In other words, absence of bleeding in P. falciparum-infected patients does not exclude the presence of DIC in this same population; actually, most of these patients meet the criteria for DIC as defined above 22 . Unfortunately, absence of bleeding is often mistakenly regarded as the reason why DIC is supposedly not present in malaria. Further, some reports do not support the view that coa...

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“…The concentrations of inhibitors were determined by referring to previous in vitro studies that used cultured cells (27)(28)(29)(30)(31)(32)(33)(34).…”

Section: Methodsmentioning

confidence: 99%

Dissecting the Factors Involved in the Locomotion Mode of Neuronal Migration in the Developing Cerebral Cortex

Nishimura

Sekiné

Chihama

et al. 2010

Journal of Biological Chemistry

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Neuronal migration is essential for proper cortical layer formation and brain function, because migration defects result in neurological disorders such as mental retardation and epilepsy. Neuronal migration is divided into several contiguous steps: early phase (multipolar mode), locomotion mode, and terminal translocation mode. The locomotion mode covers most of the migration route and thereby is the main contributor to cortical layer formation. However, analysis of the molecular mechanisms regulating this mode is difficult due to the secondary effects of defects at the early phase of migration. In this study, we established an ex vivo chemical inhibitor screening, allowing us to directly analyze the locomotion mode of migration. Roscovitine and PP2, inhibitors for Cdk5 and Src family kinases, respectively, suppressed the locomotion mode of migration. In line with this, a small percentage of Cdk5-or Src family kinase (Fyn)-knockdown cells exhibited locomoting morphology but retarded migration, although the majority of cells were stalled at the early phase of migration. We also showed that rottlerin, widely used as a specific inhibitor for protein kinase C␦ (PKC␦), suppressed the locomotion mode. Unexpectedly, however, the dominant-negative form as well as RNA interference for PKC␦ hardly affected the locomotion, whereas they may disturb terminal translocation. In addition, we found JNK to be a potential downstream target of rottlerin. Taken together, our novel chemical inhibitor screening provides evidence that Cdk5 and Src family kinases regulate the locomotion mode of neuronal migration. It also uncovered roles for Fyn and PKC␦ in the early and final phases of migration, respectively.The mammalian cerebral cortex is a six-layered structure, whose formation is largely dependent on regulated neuronal migration during developmental stages. The disruption of cortical layer structure results in several neurological disorders with mental retardation and/or epilepsy, such as lissencephaly and periventricular heterotopia in humans (1-3). In addition, recent reports indicated that schizophrenia and dyslexia are associated with neuronal migration defects (4, 5). Thus, proper regulation of neuronal migration is a pivotal step for the formation of a functional brain with a normal layered structure.During cortical development, post-mitotic neurons, generated near the ventricle, migrate toward the pial surface exhibiting various morphological changes and neuronal maturation events (3, 6). Neuronal migration is divided into several contiguous steps: the early phase of migration (the multipolar migration mode and some parts of neuronal maturation events), the locomotion mode, and the terminal translocation mode (see Fig. 1A). During the early phase of migration, the majority of post-mitotic neurons display multipolar morphology and undergo several neuronal maturation events, including neuronal polarity and axon formation, in the lower part of the intermediate zone. Subsequently, they transform into bipolar-shaped neurons with...

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Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes

Cited by 91 publications

References 35 publications

GGPPS, a New EGR-1 Target Gene, Reactivates ERK 1/2 Signaling through Increasing Ras Prenylation

GGPPS, a New EGR-1 Target Gene, Reactivates ERK 1/2 Signaling through Increasing Ras Prenylation

Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

Dissecting the Factors Involved in the Locomotion Mode of Neuronal Migration in the Developing Cerebral Cortex

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