Cytokine‐Induced Slowing of <scp>STAT3</scp> Nuclear Import; Faster Basal Trafficking of the <scp>STAT3β</scp> Isoform

Ng, Ivan Hong Wee; Bogoyevitch, Marie A.; Jans, David A.

doi:10.1111/tra.12181

Cited by 13 publications

(13 citation statements)

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“…If one accounts for ΔS splice variants, and STAT3’s ability to heterodimerize with STAT1α and β [ 35 ]; there are 18 possible STAT3 or STAT3/STAT1 dimer combinations; potentially with differing activities. Furthermore, the nuclear localization kinetics of activating STAT3α and β differ [ 36 ]. The proximity of Ser-701 to Tyr-705 (and Ser-701 phosphorylation) could mean the ΔS/S splicing decision has consequences for STAT3 dynamics.…”

Section: Discussionmentioning

confidence: 99%

Ratios of Four STAT3 Splice Variants in Human Eosinophils and Diffuse Large B Cell Lymphoma Cells

Turton

Annis

et al. 2015

PLoS ONE

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Signal transducer and activator of transcription 3 (STAT3) is a key mediator of leukocyte differentiation and proliferation. The 3' end of STAT3 transcripts is subject to two alternative splicing events. One results in either full-length STAT3α or in STAT3β, which lacks part of the C-terminal transactivation domain. The other is at a tandem donor (5') splice site and results in the codon for Ser-701 being included (S) or excluded (ΔS). Despite the proximity of Ser-701 to the site of activating phosphorylation at Tyr-705, ΔS/S splicing has barely been studied. Sequencing of cDNA from purified eosinophils revealed the presence of four transcripts (S-α, ΔS-α, S-β, and ΔS-β) rather than the three reported in publically available databases from which ΔS-β is missing. To gain insight into regulation of the two alternative splicing events, we developed a quantitative(q) PCR protocol to compare transcript ratios in eosinophils in which STAT3 is upregulated by cytokines, activated B cell diffuse large B cell Lymphoma (DLBCL) cells in which STAT3 is dysregulated, and in germinal center B cell-like DLBCL cells in which it is not. With the exception of one line of activated B cell DLCBL cells, the four variants were found in roughly the same ratios despite differences in total levels of STAT3 transcripts. S-α was the most abundant, followed by S-β. ΔS-α and ΔS-β together comprised 15.6±4.0 % (mean±SD, n=21) of the total. The percentage of STAT3β variants that were ΔS was 1.5-fold greater than of STAT3α variants that were ΔS. Inspection of Illumina’s “BodyMap” RNA-Seq database revealed that the ΔS variant accounts for 10-26 % of STAT3 transcripts across 16 human tissues, with less variation than three other genes with the identical tandem donor splice site sequence. Thus, it seems likely that all cells contain the S-α, ΔS-α, S-β, and ΔS-β variants of STAT3.

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Section: Discussionmentioning

confidence: 99%

Ratios of Four STAT3 Splice Variants in Human Eosinophils and Diffuse Large B Cell Lymphoma Cells

Turton

Annis

et al. 2015

PLoS ONE

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“…Phosphorylation of STAT3 on S727 is thought to enhance canonical transcription by increasing recruitment of the histone acetyltransferase p300 ( 1 , 44 ). S727 phosphorylation has also been implicated in the recruitment of tyrosine phosphatases, thereby attenuating canonical STAT3 signaling ( 49 , 50 ).…”

Section: Non-canonical Stat3 Signalingmentioning

confidence: 99%

“…Tyrosine phosphorylation does not affect STAT3 nuclear import; however, nuclear accumulation of STAT3 is determined by DNA binding, which is enhanced by tyrosine phosphorylation. Consequently, STAT3 S727 phosphorylation, which enhances recruitment of a tyrosine phosphatase, attenuates STAT3 nuclear accumulation ( 50 ).…”

Section: Non-canonical Stat3 Signalingmentioning

confidence: 99%

Pivotal Importance of STAT3 in Protecting the Heart from Acute and Chronic Stress: New Advancement and Unresolved Issues

Zouein

Altara

Chen

et al. 2015

Front. Cardiovasc. Med.

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The transcription factor, signal transducer and activator of transcription 3 (STAT3), has been implicated in protecting the heart from acute ischemic injury under both basal conditions and as a crucial component of pre- and post-conditioning protocols. A number of anti-oxidant and antiapoptotic genes are upregulated by STAT3 via canonical means involving phosphorylation on Y705 and S727, although other incompletely defined posttranslational modifications are involved. In addition, STAT3 is now known to be present in cardiac mitochondria and to exert actions that regulate the electron transport chain, reactive oxygen species production, and mitochondrial permeability transition pore opening. These non-canonical actions of STAT3 are enhanced by S727 phosphorylation. The molecular basis for the mitochondrial actions of STAT3 is poorly understood, but STAT3 is known to interact with a critical subunit of complex I and to regulate complex I function. Dysfunctional complex I has been implicated in ischemic injury, heart failure, and the aging process. Evidence also indicates that STAT3 is protective to the heart under chronic stress conditions, including hypertension, pregnancy, and advanced age. Paradoxically, the accumulation of unphosphorylated STAT3 (U-STAT3) in the nucleus has been suggested to drive pathological cardiac hypertrophy and inflammation via non-canonical gene expression, perhaps involving a distinct acetylation profile. U-STAT3 may also regulate chromatin stability. Our understanding of how the non-canonical genomic and mitochondrial actions of STAT3 in the heart are regulated and coordinated with the canonical actions of STAT3 is rudimentary. Here, we present an overview of what is currently known about the pleotropic actions of STAT3 in the heart in order to highlight controversies and unresolved issues.

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“…In fact, exchange of a single component within a transcription factor complex can transform it from one that activates transcription to one that represses gene expression 1 . For example, the signal transducers and activators of transcription (STATs) are a class of transcription factor that transmit signals from the plasma membrane to target genes in the nucleus, and through reversible formation of homo- or hetero-dimers, modulate the kinetics of nuclear trafficking to turn on or off gene expression 2 3 4 . Specifically, STAT3 monomers form latent dimers that shuttle between the nucleus and cytoplasm, and on phosphorylation bind consensus DNA targets to induce gene expression 4 5 .…”

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confidence: 99%

Quantifying the dynamics of the oligomeric transcription factor STAT3 by pair correlation of molecular brightness

et al. 2016

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Oligomerization of transcription factors controls their translocation into the nucleus and DNA-binding activity. Here we present a fluorescence microscopy analysis termed pCOMB (pair correlation of molecular brightness) that tracks the mobility of different oligomeric species within live cell nuclear architecture. pCOMB amplifies the signal from the brightest species present and filters the dynamics of the extracted oligomeric population based on arrival time between two locations. We use this method to demonstrate a dependence of signal transducer and activator of transcription 3 (STAT3) mobility on oligomeric state. We find that on entering the nucleus STAT3 dimers must first bind DNA to form STAT3 tetramers, which are also DNA-bound but exhibit a different mobility signature. Examining the dimer-to-tetramer transition by a cross-pair correlation analysis (cpCOMB) reveals that chromatin accessibility modulates STAT3 tetramer formation. Thus, the pCOMB approach is suitable for mapping the impact oligomerization on transcription factor dynamics.

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Cytokine‐Induced Slowing of STAT3 Nuclear Import; Faster Basal Trafficking of the STAT3β Isoform

Abstract: The STAT3 signal transducer and activator of transcription is a key medi-

Cited by 13 publications

References 50 publications

Ratios of Four STAT3 Splice Variants in Human Eosinophils and Diffuse Large B Cell Lymphoma Cells

Ratios of Four STAT3 Splice Variants in Human Eosinophils and Diffuse Large B Cell Lymphoma Cells

Pivotal Importance of STAT3 in Protecting the Heart from Acute and Chronic Stress: New Advancement and Unresolved Issues

Quantifying the dynamics of the oligomeric transcription factor STAT3 by pair correlation of molecular brightness

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