scholarly journals Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor

Oncogene ◽  
2013 ◽  
Vol 33 (9) ◽  
pp. 1158-1166 ◽  
Author(s):  
T M Becker ◽  
S C Boyd ◽  
B Mijatov ◽  
K Gowrishankar ◽  
S Snoyman ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stat3 Transcription Factor ◽  
Survival Signaling

Cellular dynamics of the STAT3 transcription factor

Cytokine ◽  
2009 ◽  
Vol 48 (1-2) ◽  
pp. 127
Author(s):  
Velasco Cimica ◽  
Janaki Iyer ◽  
Nancy C. Reich
Keyword(s):  
Transcription Factor ◽  
Cellular Dynamics ◽  
Stat3 Transcription Factor

scholarly journals Biochemical Properties of a Decoy Oligodeoxynucleotide Inhibitor of STAT3 Transcription Factor

2018 ◽  
Vol 19 (6) ◽  
pp. 1608 ◽  
Author(s):  
David Lee ◽  
Rachel O’Keefe ◽  
Patrick Ha ◽  
Jennifer Grandis ◽  
Daniel Johnson
Keyword(s):  
Transcription Factor ◽  
Biochemical Properties ◽  
Stat3 Transcription Factor

scholarly journals Association of Herpesvirus Saimiri Tip with Lipid Raft Is Essential for Downregulation of T-Cell Receptor and CD4 Coreceptor

2006 ◽  
Vol 80 (1) ◽  
pp. 108-118 ◽  
Author(s):  
Nam-Hyuk Cho ◽  
Dior Kingston ◽  
Heesoon Chang ◽  
Eun-Kyung Kwon ◽  
Jo-Min Kim ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Lipid Rafts ◽  
T Cell Receptor ◽  
Lipid Raft ◽  
Cell Receptor ◽  
Surface Expression ◽  
Herpesvirus Saimiri ◽  
Stat3 Transcription Factor ◽  
Tcr Signal Transduction

ABSTRACT Lipid rafts are membrane microdomains that are proposed to function as platforms for both receptor signaling and trafficking. Our previous studies have demonstrated that Tip of herpesvirus saimiri (HVS), which is a T-lymphotropic tumor virus, is constitutively targeted to lipid rafts and interacts with cellular Lck tyrosine kinase and p80 WD repeat-containing endosomal protein. Through the interactions with Lck and p80, HVS Tip modulates diverse T-cell functions, which leads to the downregulation of T-cell receptor (TCR) and CD4 coreceptor surface expression, the inhibition of TCR signal transduction, and the activation of STAT3 transcription factor. In this study, we investigated the functional significance of Tip association with lipid rafts. We found that Tip expression remarkably increased lipid raft fractions in human T cells by enhancing the recruitment of lipid raft-resident proteins. Genetic analysis showed that the carboxyl-terminal transmembrane, but not p80 and Lck interaction, of Tip was required for the lipid raft localization and that lipid raft localization of Tip was necessary for the efficient downregulation of TCR and CD4 surface expression. Correlated with this, treatment with Filipin III, a lipid raft-disrupting agent, effectively reversed the downregulation of CD3 and CD4 surface expression induced by Tip. On the other hand, Tip mutants that were no longer present in lipid rafts were still capable of inhibiting TCR signaling and activating STAT3 transcription factor activity as efficiently as wild-type (wt) Tip. These results indicate that the association of Tip with lipid rafts is essential for the downregulation of TCR and CD4 surface expression but not for the inhibition of TCR signal transduction and the activation of STAT3 transcription factor. These results also suggest that the signaling and targeting activities of HVS Tip rely on functionally and genetically separable mechanisms, which may independently modulate T-cell function for viral persistence or pathogenesis.

scholarly journals The cdk5 Kinase Regulates the STAT3 Transcription Factor to Prevent DNA Damage upon Topoisomerase I Inhibition

2010 ◽  
Vol 285 (35) ◽  
pp. 26765-26778 ◽  
Author(s):  
Sandy Courapied ◽  
Hélène Sellier ◽  
Sophie de Carné Trécesson ◽  
Arnaud Vigneron ◽  
Anne-Charlotte Bernard ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Topoisomerase I ◽  
Stat3 Transcription Factor

Abstract 1624: A fragment-based approach to the development of small-molecule STAT3 transcription factor inhibitors

2014 ◽  
Author(s):  
Kazi Sharmin Nahar ◽  
Christopher Chamberlain ◽  
Aanchal Grover ◽  
Paul Jackson ◽  
Khondaker M. Rahman ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Small Molecule ◽  
Stat3 Transcription Factor

SOX4 enables Oncogenic Survival Signals in Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 863-863
Author(s):  
Parham Ramezani-Rad ◽  
Huimin Geng ◽  
Lai N Chan ◽  
Christian Hurtz ◽  
Hassan Jumaa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Transcription Factor ◽  
Clinical Outcome ◽  
Mouse Model ◽  
B Cell ◽  
Myeloid Leukemia ◽  
Negative Regulation ◽  
Mrna Levels ◽  
Poor Clinical Outcome ◽  
Survival Signaling

Abstract Abstract 863 Background: The SOX4 (SRY-related HMG-box) transcription factor is expressed in early B- and T- cell development. In the absence of SOX4, B cell development is arrested at the pro-B to pre-B cell transition. In Sox4−/− mice, pro-B cells fail to proliferate in response to IL7 and to expand and differentiate past the pre-B cell receptor checkpoint. Interestingly, SOX4 functions a transcription factor yet closely interacts with membrane-proximal cytokine receptor signaling. The PDZ domain-containing adaptor protein syntenin (SDCBP) recruits the Sox4 protein directly to the cytoplasmic tail of the cytokine receptors. With regard to its receptor-proximal activation, Sox4 resembles the SMAD and STAT transcription factors. A role for Sox4 in acute myeloid leukemia was proposed based on the identification of viral insertions, and Sox4-overexpression causes myeloid leukemia. In this study, we found SOX4 was strongly upregulated upon tyrosine kinase inhibitor (TKI) treatment in Ph+ ALL and high expression of Sox4 correlates with poor clinical outcome of patients with ALL. Results: To elucidate the potential contribution of Sox4 to BCR-ABL1-driven B cell lineage leukemia, we studied a conditional Sox4 knockout mouse model. To this end, we transformed bone marrow B cell precursors from Sox4fl/fl mice with BCR-ABL1 to test its function in a mouse-model for Ph+ ALL. Tamoxifen (4-OHT)-inducible activation of Cre and subsequent deletion of loxP-flanked Sox4 alleles in B cell precursor ALL resulted in reduced mRNA levels of multiple genes that play a known role in survival signaling in Ph+ ALL cells including BCLXL (BCL2l1), Mapk8, Map2k6, PI3K/AKT (Pik3r2, Pik3r3, Rps6ka2, Mtor). Overexpression of Sox4 had the opposite effect and resulted in increased mRNA levels of BCLXL (Bcl2l1), Mapk8, PI3K/AKT (Pik3r2, Pik3r3). Single-locus quantitative ChIP confirmed binding of SOX4 to BCL2l1, PIK3R3 and MAPK8 promoters in human Ph+ ALL cells via its putative DNA binding motif. Transcriptional regulation of components within the PI3K/AKT pathway is indeed functionally relevant since Cre-mediated deletion of Sox4 caused multiple de-phosphorylation events including AKTS473, SRCY416 and RPS6S235/6. In addition, inducible deletion of Sox4 resulted in strong upregulation of both Arf and p53 protein, suggesting that Sox4 mediates survival signaling both by activation of BCLXL (Bcl2l1) and repression of Arf/p53. Consistent with Sox4-mediated negative regulation of Arf/p53, deletion of Sox4 resulted in G0/G1 arrest of BCR-ABL1 ALL cells and loss of self-renewal capacity, failure to form colonies in methylcellulose replating assays and delayed the onset of disease and substantially prolonged overall survival of recipient mice. In agreement with reduced expression of BCLXL (Bcl2l1) and increased levels of Arf/p53, the overall outcome of Sox4 deletion is rapid loss of viability and apoptosis in BCR-ABL1-transformed ALL but not normal pre-B cells. Loss of viability upon Sox4 deletion in the leukemia cells was rescued by transduction with constitutively active (myristoylated; CA) mutants of AKTCA and the p110 catalytic subunit of PI3K (p110αCA) and as well with BCLXL. Clinical relevance: These findings are also relevant to human disease since promoter CpG methylation analysis (HELP assay) revealed lower levels SOX4 promoter methylation in human Ph+ALL cells compared to their normal pre-B cell counterparts. In addition, samples from patients with high risk ALL (n=31) show a trend towards higher SOX4 mRNA levels compared to patients with intermediate risk ALL (n=23, p=0.07; ALL REZ BFM 2002). Analyzing data from a larger study based on 207 patients with ALL (COG P9906) showed a statistically significant association between high mRNA levels of SOX4 and poor clinical outcome (shorter overall survival). Conclusion: Collectively, these findings identify SOX4 as a critical upstream regulator of survival signaling in Ph+ ALL. Pathways affected by SOX4 include PI3K/AKT signaling downstream of BCR-ABL1, activation of BCLXL (BCL2L1) and negative regulation of Arf and p53. Disclosures: No relevant conflicts of interest to declare.

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