Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

Cui, Xiaoyan; Zhang, L; Luo, Jie; Rajasekaran, Ayyappan K.; Hazra, Saswati; Cacalano, Nicholas A.; Dubinett, Steven M.

doi:10.1038/sj.onc.1210222

Cited by 63 publications

(51 citation statements)

References 26 publications

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“…7). In contrast to our results, previous reports indicated that IL-4-induced STAT6 represses COX-2 in human follicular dendritic cells (53), and unphosphorylated STAT6 contributes to constitutive COX-2 expression in lung cancer (54). STAT6 is overexpressed in several human malignancies, including prostate and colon cancer, lymphoma, leukemia, and glioma (16,55,56).…”

Section: Discussioncontrasting

confidence: 55%

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

Park

Lee

Kim

et al. 2012

The Journal of Immunology

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Emerging evidence has established that astrocytes, once considered passive supporting cells that maintained extracellular ion levels and served as a component of the blood–brain barrier, play active regulatory roles during neurogenesis and in brain pathology. In the current study, we demonstrated that astrocytes sense H2O2 by rapidly phosphorylating the transcription factor STAT6, a response not observed in microglia. STAT6 phosphorylation was induced by generators of other reactive oxygen species (ROS) and reactive nitrogen species, as well as in the reoxygenation phase of hypoxia/reoxygenation, during which ROS are generated. Src–JAK pathways mediated STAT6 phosphorylation upstream. Experiments using lipid raft disruptors and analyses of detergent-fractionated cells demonstrated that H2O2-induced STAT6 phosphorylation occurred in lipid rafts. Under experimental conditions in which H2O2 did not affect astrocyte viability, H2O2-induced STAT6 phosphorylation resulted in STAT6-dependent cyclooxygenase-2 expression and subsequent release of PGE2 and prostacyclin, an effect also observed in hypoxia/reoxygenation. Finally, PGs released from H2O2-stimulated astrocytes inhibited microglial TNF-α expression. Accordingly, our results indicate that ROS-induced STAT6 phosphorylation in astrocytes can modulate the functions of neighboring cells, including microglia, through cyclooxygenase-2 induction and subsequent release of PGs. Differences in the sensitivity of STAT6 in astrocytes (highly sensitive) and microglia (insensitive) to phosphorylation following brief exposure to H2O2 suggest that astrocytes can act as sentinels for certain stimuli, including H2O2 and ROS, refining the canonical notion that microglia are the first line of defense against external stimuli.

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Section: Discussioncontrasting

confidence: 55%

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

Park

Lee

Kim

et al. 2012

The Journal of Immunology

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“…A previous study has shown that unphosphorylated STAT family proteins play a role as active transcription factors: unphosphorylated STAT3 cooperates with NF-κB to induce RANTES (also known as CCL5) gene expression (Yang et al, 2007(Yang et al, , 2005 and unphosphorylated STAT6 forms a complex with p300 (also known as EP300) to upregulate the cyclooxygenase-2 gene (Cui et al, 2007). To describe the transcriptional pattern and the complicated cellular biological processes of unphosphorylated STAT1, exploring its binding partners and networks of protein is necessary.…”

Section: Discussionmentioning

confidence: 99%

Unphosphorylated STAT1 represses apoptosis in macrophages during Mycobacterium t uberculosis infection

Yao

Chen

et al. 2017

Journal of Cell Science

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In murine macrophages infected with Mycobacterium tuberculosis (Mtb), the level of phosphorylated STAT1 (P-STAT1), which drives the expression of many pro-apoptosis genes, increases quickly but then declines over a period of hours. By contrast, infection induces a continued increase in the level of unphosphorylated STAT1 that persists for several days. Here, we found that the level of unphosphorylated STAT1 correlated with the intracellular bacterial burden during the later stages of infection. To investigate the significance of a high level of unphosphorylated STAT1, we increased its concentration exogenously, and found that the apoptosis rate induced by Mtb was sufficiently decreased. Further experiments confirmed that unphosphorylated STAT1 affects the expression of several immune-associated genes and lessens the sensitivity of macrophages to CD95 (FAS)-mediated apoptosis during Mtb infection. Furthermore, we characterized 149 proteins that interacted with unphosphorylated STAT1 and the interactome network. The cooperation between unphosphorylated STAT1 and STAT3 results in downregulation of CD95 expression. Additionally, we verified that unphosphorylated STAT1 and IFIT1 competed for binding to eEF1A. Taken together, our data show that the role of unphosphorylated STAT1 differs from that of P-STAT1, and represses apoptosis in macrophages to promote immune evasion during Mtb infection.

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“…of studies indicate unphosphorylated STATs function in nuclear gene expression (Chatterjee-Kishore et al, 2000;Cui et al, 2007;Yang et al, 2005;Yang and Stark, 2008). In addition, nuclear import of STAT3, STAT5, and STAT6 has been shown to be independent of tyrosine phosphorylation (Chen and Reich, 2010;Cimica et al, 2011;Iyer and Reich, 2008;Liu et al, 2005;Meyer and Vinkemeier, 2004;Zeng et al, 2002).…”

Section: Stat5a Nuclear Trafficking 3339mentioning

confidence: 99%

Dynamic Trafficking of STAT5 Depends on an Unconventional Nuclear Localization Signal

Shin

Reich

2013

Journal of Cell Science

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SummarySignal transducer and activator of transcription 5 (STAT5) is crucial for physiological processes that include hematopoiesis, liver metabolism and mammary gland development. However, aberrant continual activity of STAT5 has been causally linked to human leukemias and solid tumor formation. As a regulated transcription factor, precise cellular localization of STAT5 is essential. Conventional nuclear localization signals consist of short stretches of basic amino acids. In this study, we provide evidence that STAT5 nuclear import is dependent on an unconventional nuclear localization signal that functions within the conformation of an extensive coiled-coil domain. Both in vitro binding and in vivo functional assays reveal that STAT5 nuclear import is mediated by the importin-a3/ b1 system independently of STAT5 activation by tyrosine phosphorylation. The integrity of the coiled-coil domain is essential for STAT5 transcriptional induction of the b-casein gene following prolactin stimulation as well as its ability to synergize with the glucocorticoid receptor. The glucocorticoid receptor accumulates in the nucleus in response to prolactin and this nuclear import is dependent on STAT5 nuclear import. STAT5 continually shuttles in and out of the nucleus and live cell imaging demonstrates that STAT5 nuclear export is mediated by both chromosome region maintenance 1 (Crm1)-dependent and Crm1-independent pathways. A Crm1-dependent nuclear export signal was identified within the STAT5 N-terminus. These findings provide insight into the fundamental mechanisms that regulate STAT5 nuclear trafficking and cooperation with the glucocorticoid receptor and provide a basis for clinical intervention of STAT5 function in disease.

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Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

Cited by 63 publications

References 26 publications

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

Unphosphorylated STAT1 represses apoptosis in macrophages during Mycobacterium t uberculosis infection

Dynamic Trafficking of STAT5 Depends on an Unconventional Nuclear Localization Signal

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