Molecular dynamics simulations of the conformational changes in signal transducers and activators of transcription, Stat1 and Stat3

Lin, Jianping; Buettner, Ralf; Yuan, Yate-Ching; Yip, Richard; Horne, David; Jove, Richard; Vaidehi, Nagarajan

doi:10.1016/j.jmgm.2009.08.013

Cited by 23 publications

(28 citation statements)

References 29 publications

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“…In this paper, 3D structural analyses of the protein/DNA interaction of STAT1 and STAT3 demonstrated their high similarity, confirming previous reports [13]. These 3D analyses served as a basis for the design of new sequences with base substitutions.…”

Section: Discussionsupporting

confidence: 89%

“…Its biological function is thus mostly antagonistic to that of STAT3. Despite their 50% amino acid sequence homology [13], STAT1 and STAT3 are structurally very similar; yet some important differences have been noted in their DBD sequences [14]. Despite its major role as a tumor antagonist, STAT1 can also have functions in cancer cells, as documented in mouse leukemia [15].…”

Section: Introductionmentioning

confidence: 99%

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A STAT3-inhibitory hairpin decoy oligodeoxynucleotide discriminates between STAT1 and STAT3 and induces death in a human colon carcinoma cell line

et al. 2012

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BackgroundThe Signal Transducer and Activator of Transcription 3 (STAT3) is activated in tumor cells, and STAT3-inhibitors are able to induce the death of those cells. Decoy oligodeoxynucleotides (dODNs), which bind to the DNA Binding Domain (DBD) of STAT3, are efficient inhibitors. However, they also inhibit STAT1, whose activity is essential not only to resistance to pathogens, but also to cell growth inhibition and programmed cell death processes. The aim of this study was to design STAT3-specific dODNs which do not affect STAT1-mediated processes.ResultsNew dODNs with a hairpin (hpdODNs) were designed. Modifications were introduced, based on the comparison of STAT3- and STAT1-DBD interactions with DNA using 3D structural analyses. The designed hpdODNs were tested for their ability to inhibit STAT3 but not STAT1 by determining: i) cell death in the active STAT3-dependent SW480 colon carcinoma cell line, ii) absence of inhibition of interferon (IFN) γ-dependent cell death, iii) expression of STAT1 targets, and iv) nuclear location of STAT3 and STAT1. One hpdODN was found to efficiently induce the death of SW480 cells without interfering with IFNγ-activated STAT1. This hpdODN was found in a complex with STAT3 but not with STAT1 using an original in-cell pull-down assay; this hpdODN also did not inhibit IFNγ-induced STAT1 phosphorylation, nor did it inhibit the expression of the STAT1-target IRF1. Furthermore, it prevented the nuclear transfer of STAT3 but not that of IFNγ-activated STAT1.ConclusionsComparative analyses at the atomic level revealed slight differences in STAT3 and STAT1 DBDs' interaction with their DNA target. These were sufficient to design a new discriminating hpdODN that inhibits STAT3 and not STAT1, thereby inducing tumor cell death without interfering with STAT1-dependent processes. Preferential interaction with STAT3 depends on oligodeoxynucleotide sequence modifications but might also result from DNA shape changes, known to modulate protein/DNA interactions. The finding of a STAT3-specific hpdODN establishes the first rational basis for designing STAT3 DBD-specific inhibitors.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

A STAT3-inhibitory hairpin decoy oligodeoxynucleotide discriminates between STAT1 and STAT3 and induces death in a human colon carcinoma cell line

et al. 2012

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“…However, our results showed that YFV NS5 associated with STAT2 in response to IFN-I treatment when cells were reconstituted with wild-type but not mutant (Y701F) STAT1. Given that tyrosine phosphorylation induces STAT1/2 heterodimers to transform from a parallel to an antiparallel association with respect to their C- and N-termini (Lin et al, 2009), these results suggest that the NS5 binding domain is only exposed when STAT2 interacts with phosphorylated STAT1 resulting in a different STAT2 conformation. Thus, our results indicate that IFN-I promotes YFV NS5/STAT2 interaction by inducing STAT1 tyrosine phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

The Interferon Signaling Antagonist Function of Yellow Fever Virus NS5 Protein Is Activated by Type I Interferon

Laurent-Rolle

Morrison

Rajsbaum

et al. 2014

Cell Host & Microbe

139

156

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Summary To successfully establish infection Flaviviruses have to overcome the antiviral state induced by type I interferon (IFN-I). The nonstructural NS5 proteins of several flaviviruses antagonize IFN-I signaling. Here we show that yellow fever virus (YFV) inhibits IFN-I signaling through a unique mechanism that involves binding of YFV NS5 to the IFN-activated transcription factor STAT2 only in cells that have been stimulated with IFN-I. This NS5-STAT2 interaction requires IFN-I-induced tyrosine phosphorylation of STAT1 and the K63-linked polyubiquitination at a lysine in the N-terminal region of YFV NS5. We identified TRIM23 as the E3 ligase that interacts with and polyubiquitinates YFV NS5 to promote its binding to STAT2 and trigger IFN-I signaling inhibition. Our results demonstrate the importance of YFV NS5 in overcoming the antiviral action of IFN-I and offer a unique example of a viral protein that is activated by the same host pathway that it inhibits.

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“…We obtained the similar result in another cervical cancer cell line C33A cells. Since there is a high degree of homology between STAT1 and STAT3 [25], we examined the phosphorylation of STAT1 to determine if BLCAP had the same inhibition effect on STAT1. Both p-STAT1 and p-STAT3 showed a strongest expression after IFN-α stimulated for 30 minutes.…”

Section: Resultsmentioning

confidence: 99%

A-to-I RNA editing of BLCAP lost the inhibition to STAT3 activation in cervical cancer

Chen

Cai

et al. 2017

Oncotarget

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Bladder cancer-associated protein (BLCAP) gene is a highly conserved gene with tumor-suppressor function in different carcinomas. It is also a novel ADAR-mediated editing substrate undergoes multiple A-to-I RNA editing events. Although the anti-tumorigenic role of BLCAP has been examined in preliminarily studies, the relationship between BLCAP function and A-to-I RNA editing in cervical carcinogenesis still require further exploration. Herein, we analyzed the coding sequence of BLCAP transcripts in 35 paired cervical cancer samples using high-throughput sequencing. Of note, editing levels of three novel editing sites were statistically different between cancerous and adjacent cervical tissues, and editing of these three sites was closely correlated. Moreover, two editing sites of BLCAP coding region were mapped-in the key YXXQ motif which can bind to SH2 domain of STAT3. Further studies revealed that BLCAP interacted with signal transducer and activator of transcription 3 (STAT3) and inhibited its phosphorylation, while A-to-I RNA editing of BLCAP lost the inhibition to STAT3 activation in cervical cancer cell lines. Our findings reveal that A-to-I RNA editing events alter the genetically coded amino acid in BLCAP YXXQ motif, which drive the progression of cervical carcinogenesis through regulating STAT3 signaling pathway.

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Molecular dynamics simulations of the conformational changes in signal transducers and activators of transcription, Stat1 and Stat3

Cited by 23 publications

References 29 publications

A STAT3-inhibitory hairpin decoy oligodeoxynucleotide discriminates between STAT1 and STAT3 and induces death in a human colon carcinoma cell line

A STAT3-inhibitory hairpin decoy oligodeoxynucleotide discriminates between STAT1 and STAT3 and induces death in a human colon carcinoma cell line

The Interferon Signaling Antagonist Function of Yellow Fever Virus NS5 Protein Is Activated by Type I Interferon

A-to-I RNA editing of BLCAP lost the inhibition to STAT3 activation in cervical cancer

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