The Duration of Nuclear Extracellular Signal-Regulated Kinase 1 and 2 Signaling during Cell Cycle Reentry Distinguishes Proliferation from Apoptosis in Response to Asbestos

Yuan, Ziqiang; Taatjes, Douglas J.; Mossman, Brooke T.; Heintz, Nicholas H.

doi:10.1158/0008-5472.can-04-0946

Cited by 33 publications

(27 citation statements)

References 29 publications

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“…We have previously demonstrated that ERK1/2 is persistently phosphorylated in response to crocidolite asbestos in lung epithelial cells (3,40). Here, we show that crocidolite asbestosmediated ERK1/2 activation is partially responsible for crocidolite asbestos-induced CREB phosphorylation.…”

Section: Discussionsupporting

confidence: 56%

Asbestos-mediated CREB phosphorylation is regulated by protein kinase A and extracellular signal-regulated kinases 1/2

Barlow

Barrett²,

Shukla³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Asbestos is a ubiquitous, naturally occurring fiber that has been linked to the development of malignant and fibrotic lung diseases. Asbestos exposure leads to apoptosis, followed by compensatory proliferation, yet many of the signaling cascades coupled to these outcomes are unclear. Because CREs (Ca2+/cAMP-response elements) are found in the promoters of many genes important for regulation of proliferation and apoptosis, CREB (CRE binding protein) is likely to play an important role in the development of asbestos-mediated lung injury. To explore this possibility, we tested the hypotheses that asbestos exposure leads to CREB phosphorylation in lung epithelial cells and that protein kinase A (PKA) and extracellular signal-regulated kinases 1/2 (ERK1/2) are central regulators of the CREB pathway. Persistent CREB phosphorylation was observed in lung sections from mice following inhalation of crocidolite asbestos. Exposure of C10 lung epithelial cells to crocidolite asbestos led to rapid CREB phosphorylation and apoptosis that was decreased by the inhibition of PKA or ERK1/2 using the specific inhibitors H89 and U0126, respectively. Furthermore, crocidolite asbestos selectively induced a sustained increase in MAP kinase phosphatase-1 mRNA and protein. Silencing CREB protein dramatically reduced asbestos-mediated ERK1/2 phosphorylation, yet significantly increased the number of cells undergoing asbestos-induced apoptosis. These data reveal a novel and selective role for CREB in asbestos-mediated signaling through pathways regulated by PKA and ERK1/2, further providing evidence that CREB is an important regulator of apoptosis in asbestos-induced responses of lung epithelial cells.

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Section: Discussionsupporting

confidence: 56%

Asbestos-mediated CREB phosphorylation is regulated by protein kinase A and extracellular signal-regulated kinases 1/2

Barlow

Barrett²,

Shukla³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In lung epithelial cells, activation of ERK1/2 is required for expression of cyclin D1 and cell proliferation in response to serum growth factors (40). Oxidants prolong signaling through ERK1/2, which stabilizes c-Fos and induces cell cycle arrest by preventing the expression of cyclin D1.…”

Section: Asbestos Fibers Activate the Epidermal Growth Factor Receptomentioning

confidence: 99%

“…The induction of apoptosis by asbestos, an event that can lead to compensatory cell proliferation, and the importance of apoptosis in therapeutic approaches for eradication of MM and lung cancer cells have been widely studied and appear multi-faceted. For example, several pathways including: (1) an intrinsic or mitochondriaregulated pathway that may be p53 or protein kinase C dependent (52-54); (2) extrinsic pathways induced by death-receptor ligands such as TNF-a or FasL (55); and (3) cell signaling via AKT, prolonged activation of ERKs, and other MAPKs (40,(56)(57)(58) have been documented by asbestos and chemotherapeutic drugs in mesothelial cells, MM cells, and lung epithelial cells in vitro. In these studies, oxidative stress appears to be a central mechanism in the induction of apoptotic pathways triggered by asbestos fibers.…”

Section: Pro-apoptotic Mechanisms Of Asbestosmentioning

confidence: 99%

Asbestos, Lung Cancers, and Mesotheliomas

Heintz

Janssen–Heininger

Mossman

2010

Am J Respir Cell Mol Biol

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154

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Fifteen years have passed since we published findings in the AJRCMB demonstrating that induction of early response fos/jun protooncogenes in rodent tracheal and mesothelial cells correlates with fibrous geometry and pathogenicity of asbestos. Our study was the first to suggest that the aberrant induction of signaling responses by crocidolite asbestos and erionite, a fibrous zeolite mineral associated with the development of malignant mesotheliomas (MMs) in areas of Turkey, led to altered gene expression. New data questioned the widely held belief at that time that the carcinogenic effects of asbestos in the development of lung cancer and MM were due to genotoxic or mutagenic effects. Later studies by our group revealed that proto-oncogene expression and several of the signaling pathways activated by asbestos were redox dependent, explaining why antioxidants and antioxidant enzymes were elevated in lung and pleura after exposure to asbestos and how they alleviated many of the phenotypic and functional effects of asbestos in vitro or after inhalation. Since these original studies, our efforts have expanded to understand the interface between asbestos-induced redox-dependent signal transduction cascades, the relationship between these pathways and cell fate, and the role of asbestos and cell interactions in development of asbestos-associated diseases. Of considerable significance is the fact that the signal transduction pathways activated by asbestos are also important in survival and chemoresistance of MMs and lung cancers. An understanding of the pathogenic features of asbestos fibers and dysregulation of signaling pathways allows strategies for the prevention and therapy of asbestos-related diseases.

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“…In vitro, phosphorylated ERK1/2 is translocated to the nucleus of C10 alveolar epithelial cells after addition of asbestos fibers, and the time frame of this process determines cell fate (35). At low, proliferative concentrations of asbestos fibers, there is an initial nuclear accumulation of phosphorylated ERK1/2 that diminishes over time and culminates in increased expression of cyclin D1 and in the entry of cells into S phase.…”

Section: A Mechanistic Model For Cigarette Smoke and Asbestos In Mapkmentioning

confidence: 99%

Oxidants and Signaling by Mitogen-Activated Protein Kinases in Lung Epithelium

Mossman

Lounsbury²,

Reddy³

2006

Am J Respir Cell Mol Biol

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149

121

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Oxidants in cigarette smoke and generated from asbestos fibers activate mitogen-activated protein kinase (MAPK) signaling cascades in lung epithelial cells in vitro and in vivo. These signaling pathways lead to the enhanced ability of Jun and Fos family members (i.e., components of the activator protein [AP]-1 transcription factor) to activate transcription of a number of AP-1-dependent target genes involved in cell proliferation or death, differentiation, and inflammation. Research by the Basbaum laboratory has been critical in showing that mucin transcription in response to cigarette smoke and gram-positive bacteria is mediated through activation of the epidermal growth factor receptor and MAPK cascades. Work from our laboratories supports the concept that MAPK signaling and AP-1 transactivation by cigarette smoke and asbestos may synergize in lung epithelial cell injury, compensatory proliferation of lung epithelial cells, and carcinogenesis, supporting a mechanistic framework for the striking increases in lung cancer incidence in asbestos workers who smoke. Targeting of MAPKs and inter-related signaling cascades may be critical to the prevention of lung cancers and control of mucin overproduction in a number of lung diseases including asthma, cystic fibrosis, chronic bronchitis, and chronic obstructive pulmonary disease.Keywords: activator protein-1; asbestos; cigarette smoke; epidermal growth factor receptor; extracellular signal regulated kinases Reactive oxygen species (ROS) and reactive nitrogen species are mediators of cell signaling in airway and pulmonary epithelial cells by a variety of toxic agents, including asbestos and silica, cigarette smoke, airborne particulate matter, diesel exhaust, and ozone. These signaling cascades are under intense investigation by a number of laboratories because of their links to exacerbation of epithelial cell injury and proliferation, cell survival and chemoresistance, altered differentiation, and production of chemokines or cytokines mediating inflammation.The mitogen-activated protein kinase (MAPK) cascades consist of serine threonine kinases that are sequentially phosphorylated by upstream kinases (MAPKKK, MAPKK) and subdivided into three major pathways: extracellular signal-regulated kinases (ERKs), c-Jun-NH 2 -terminal kinases (JNKs 1, 2, and 3) (also referred to as stress-activated protein kinases), and p38 kinases (1-3) (Figure 1). MAPK cascades can be initiated by activation of receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) or other factors stimulating phosphorylation of upstream MAPKKK and MAPKK. Because the MAPK cascades involve sequential phosphorylation of protein kinases, factors inhibiting the phosphatases that normally check these pathways also cause net increases in the phosphorylation (i.e., activation) of MAPK proteins.Specific MAPKs control the activation of fos and jun family protooncogenes and their protein products (c-Jun, Jun B, Jun D, c-Fos, Fos B, Fra-1, and Fra-2) that are also known as AP-1 family members. The...

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The Duration of Nuclear Extracellular Signal-Regulated Kinase 1 and 2 Signaling during Cell Cycle Reentry Distinguishes Proliferation from Apoptosis in Response to Asbestos

Cited by 33 publications

References 29 publications

Asbestos-mediated CREB phosphorylation is regulated by protein kinase A and extracellular signal-regulated kinases 1/2

Asbestos-mediated CREB phosphorylation is regulated by protein kinase A and extracellular signal-regulated kinases 1/2

Asbestos, Lung Cancers, and Mesotheliomas

Oxidants and Signaling by Mitogen-Activated Protein Kinases in Lung Epithelium

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