Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe

Assessment of primary radical hysterectomy and neoadjuvant chemotherapy followed by radical hysterectomy in Stage IB2, IIA bulky cervical cancer

WOS: 000362053600016PubMed ID: 26513887Objective: Uncertainty concerning the treatment of Stage IB2-IIA (bulky) cervical cancer is still continuing. In this study, an analysis of Stage IB2-IIA (bulky) cervical cancer was performed. The efficacy of primary radical surgery and neoadjuvant chemotherapy followed by a radical surgery was investigated. Materials and Methods: Medical data of 50 patients who were diagnosed with Stage IB2-IIA (bulky) cervical cancer and treated between 2002-2009 were retrospectively assessed. In the radical surgery group, radical hysterectomy + bilateral pelvic + para-aortic lymphadenectomy were performed. In the neoadjuvant chemotherapy group, a combination of cisplatin/topotecan or paclitaxel/carboplatin was given to the patients and then radical surgery was performed. Each group was evaluated individually. Prognostic factors were determined and survival rates were compared between the groups. Ap value was taken <0.05 for the statistical significance level for all results. Results: Radical surgery after neoadjuvant chemotherapy was performed in 21 and primary radical surgery in 29 patients. Median follow-up time was 36.0 +/- 14.0 months. Average of the tumor size before treatment was 50.2 +/- 7.6 mm. In the radical surgery after neoadjuvant chemotherapy group, lymphovascular space invasion (LVSI) and tumor size (before and after treatment) were determined to be significant factors for each of disease-free survival (DFS) and overall survival (OS). On multivariate analysis, tumor size (before treatment) was found to be an independent prognostic factor for both of DFS (p = 0.006) and OS (p = 0.010). No significant difference in survival periods was observed among the groups. Conclusion: There was no significant superiority among the two treatment options. Nonetheless, further studies are needed to compare the multimodal approaches in these stages of cervical cancer