Janus kinase 1/signal transducers and activators of transcription 3 (JAK1/STAT3) pathway is one of the recognized oncogenic
signaling pathways that frequently overactivated in a variety of human tumors. Despite rapid progress in elucidating the molecular
mechanisms of activation of JAK/STAT pathway, the processes that regulate JAK/STAT deactivation need to be further clarified.
Here we demonstrate that CUE domain-containing 2 (CUEDC2) inhibits cytokine-induced phosphorylation of JAK1 and STAT3 and
the subsequent STAT3 transcriptional activity. Further analysis by a yeast two-hybrid assay showed that CUEDC2 could engage
in a specific interaction with a key JAK/STAT inhibitor, SOCS3 (suppressors of cytokine signaling 3). The interaction between
CUEDC2 and SOCS3 is required for the inhibitory effect of CUEDC2 on JAK1 and STAT3 activity. Additionally, we found CUEDC2
functions collaboratively with SOCS3 to inhibit JAK1/STAT3 signaling by increasing SOCS3 stability via enhancing its association
with Elongin C. Therefore, our findings revealed a new biological activity for CUEDC2 as the regulator of JAK1/STAT3 signaling
and paved the way to a better understanding of the mechanisms by which SOCS3 has been linked to suppression of the JAK/STAT
"Another research indicated that CUEDC2 could act as an adaptor protein to target IB kinase (IKK) for dephosphorylation and inactivation by recruiting protein phosphatase (PP1), and thus repressed activation of the transcription factor NF-B . Moreover, CUEDC2 has also been found to be a novel regulator of JAK1/STAT3 signaling, through binding to SOCS3 to increase its stability and thus inhibiting JAK1/STAT3 signaling . However, the role of CUEDC2 in CML remains unclear, and thus need to be clarified. "
[Show abstract][Hide abstract] ABSTRACT: CUEDC2, a newly reported protein, has been found to be ubiquitously expressed in human tissues and repress NF-κB activity. To study the role of CUEDC2 in chronic myeloid leukemia (CML), we explored the function of CUEDC2 in CML cells through using the CML cell line K562 and its imatinib resistant cells K562/G01. K562 cells expressed a relatively higher level of CUEDC2 compared to K562/G01 cells. Knockdown of CUEDC2 in K562 cells resulted in decreased cell apoptosis after imatinib treatment; when CUEDC2 was overexpressed in K562/G01 cells, imatinib induced more cell apoptosis. By analyzing the activity of NF-κB, the results indicated a negative association between the expression of CUEDC2 and NF-κB signaling pathway in these CML cells. Our data suggested that the expression level of CUEDC2 has an inverse correlation with imatinib resistance and activity of NF-κB signaling pathway in CML cells, CUEDC2 could regulate imatinib sensitivity in CML cells at least partially through NF-κB signaling pathway.
Leukemia research 09/2013; 37(11). DOI:10.1016/j.leukres.2013.08.019 · 2.35 Impact Factor
"To investigate the functional consequences of the interaction between TRAF6 and STAT3, we examined the effect of TRAF6 on the transcriptional activation of STAT3 using luciferase reporter genes that was under the control of the STAT3 response element. HEK293 cells were transfected with TRAF6 and m67-Luc (a synthetic STAT3-responsive promoter) . As shown, overexpression of TRAF6 deactivated the transcriptional activity of STAT3 induced by the stimulation of the IFNα (Fig. 2A). "
[Show abstract][Hide abstract] ABSTRACT: STAT3 is a key transcription factor that mediates various cellular and organismal processes, such as cell growth, apoptosis, immune response and cancer. However, the molecular mechanisms of STAT3 regulation remain poorly understood. Here, we identified TRAF6 as a new STAT3 interactor. TRAF6 augmented the ubiquitination of STAT3 and deactivated its transcriptional activity induced by IFNα stimulation or overexpressed with JAK2. Both the RING domain and the TRAF-type zinc finger domain of TRAF6 were indispensable for STAT3 deactivation. Accordingly, TRAF6 also down-regulated the expression of two known STAT3 target genes, CRP and ACT. Therefore, we showed that TRAF6 is a new regulator of JAK/STAT signaling and provide a new mechanistic explanation for the crosstalk between the NF-κB and the JAK-STAT pathways.
PLoS ONE 11/2012; 7(11):e49567. DOI:10.1371/journal.pone.0049567 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) is a critical transcriptional factor in a variety of cellular processes, and is frequently over-activated in a range of human tumors. However, the processes that regulate STAT3 activation need to be further clarified. With a yeast two-hybrid screening, we identified enoyl-CoA hydratase short chain 1 (ECHS1) as a novel STAT3 binding protein. We further confirmed the interaction between STAT3 and ECHS1 by GST-pull down and co-immnunoprecipitation. Importantly, we found that ECHS1 specifically represses STAT3 activity and negatively regulates the expression of several target genes of STAT3 through inhibiting STAT3 phosphorylation. Therefore, our findings will provide new insights into the mechanism of STAT3 signaling regulation. STRUCTURED SUMMARY OF PROTEIN INTERACTIONS: STAT3physically interactswithECHS1bypull down(View interaction) STAT3physically interactswithECHS1bytwo hybrid(View Interaction:1,2) ECHS1physically interactswithSTAT3byanti tag co immunoprecipitation(View Interaction:1,2) STAT3physically interactswithECHS1byanti bait co immunoprecipitation(View interaction).
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