scholarly journals Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2

2021 ◽  
Vol 118 (11) ◽  
pp. e2022779118
Author(s):  
Rengyun Liu ◽  
Jie Tan ◽  
Xiaopei Shen ◽  
Ke Jiang ◽  
Chaoqun Wang ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Cell Apoptosis ◽  
Human Cancer ◽  
Critical Role ◽  
Transcriptional Factor ◽  
Wild Type ◽  
Key Players ◽  
Related Proteins ◽  
Necrosis Factor ◽  
Apoptotic Cascade

The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) TERT cascade plays a critical role in the regulation of mutant TERT, in which FOS acts as a transcriptional factor for GABPB to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type TERT promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant TERT cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type TERT cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) and inactivation of survivin, two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of survivin, up-regulating its expression. Thus, this study identifies a therapeutic strategy for TERT promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) TERT cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.

scholarly journals Transformation properties of the E2a-Pbx1 chimeric oncoprotein: fusion with E2a is essential, but the Pbx1 homeodomain is dispensable.

1994 ◽  
Vol 14 (12) ◽  
pp. 8304-8314 ◽  
Author(s):  
K Monica ◽  
D P LeBrun ◽  
D A Dedera ◽  
R Brown ◽  
M L Cleary
Keyword(s):  
Transcriptional Activation ◽  
Binding Sites ◽  
Chromosomal Translocation ◽  
Wild Type ◽  
3T3 Cells ◽  
Homeodomain Proteins ◽  
Malignant Lymphomas ◽  
Oncogenic Potential ◽  
Related Proteins ◽  
Nih 3T3

The t(1;19) chromosomal translocation in acute lymphoblastic leukemias creates chimeric E2a-Pbx1 oncoproteins that can act as DNA-binding activators of transcription. A structural analysis of the functional domains of E2a-Pbx1 showed that portions of both E2a and Pbx1 were essential for transformation of NIH 3T3 cells and transcriptional activation of synthetic reporter genes containing PBX1 consensus binding sites. Hyperexpression of wild-type or experimentally truncated Pbx1 proteins was insufficient for transformation, consistent with their inability to activate transcription. When fused with E2a, the Pbx-related proteins Pbx2 and Pbx3 were also transformation competent, demonstrating that all known members of this highly similar subfamily of homeodomain proteins have latent oncogenic potential. The oncogenic contributions of E2a to the chimeras were localized to transactivation motifs AD1 and AD2, as their mutation significantly impaired transformation. Either the homeodomain or Pbx1 amino acids flanking this region could mediate transformation when fused to E2a. However, the homeodomain was not essential for transformation, since a mutant E2a-Pbx1 protein (E2a-Pbx delta HD) lacking the homeodomain efficiently transformed fibroblasts and induced malignant lymphomas in transgenic mice. Thus, transformation mediated by the chimeric oncoprotein E2a-Pbx1 is absolutely dependent on motifs acquired from E2a but the Pbx1 homeodomain is optional. The latter finding suggests that E2a-Pbx1 may interact with cellular proteins that assist or mediate alterations in gene expression responsible for oncogenesis even in the absence of homeodomain-DNA interactions.

Transformation properties of the E2a-Pbx1 chimeric oncoprotein: fusion with E2a is essential, but the Pbx1 homeodomain is dispensable

1994 ◽  
Vol 14 (12) ◽  
pp. 8304-8314
Author(s):  
K Monica ◽  
D P LeBrun ◽  
D A Dedera ◽  
R Brown ◽  
M L Cleary
Keyword(s):  
Transcriptional Activation ◽  
Binding Sites ◽  
Chromosomal Translocation ◽  
Wild Type ◽  
3T3 Cells ◽  
Homeodomain Proteins ◽  
Malignant Lymphomas ◽  
Oncogenic Potential ◽  
Related Proteins ◽  
Nih 3T3

The t(1;19) chromosomal translocation in acute lymphoblastic leukemias creates chimeric E2a-Pbx1 oncoproteins that can act as DNA-binding activators of transcription. A structural analysis of the functional domains of E2a-Pbx1 showed that portions of both E2a and Pbx1 were essential for transformation of NIH 3T3 cells and transcriptional activation of synthetic reporter genes containing PBX1 consensus binding sites. Hyperexpression of wild-type or experimentally truncated Pbx1 proteins was insufficient for transformation, consistent with their inability to activate transcription. When fused with E2a, the Pbx-related proteins Pbx2 and Pbx3 were also transformation competent, demonstrating that all known members of this highly similar subfamily of homeodomain proteins have latent oncogenic potential. The oncogenic contributions of E2a to the chimeras were localized to transactivation motifs AD1 and AD2, as their mutation significantly impaired transformation. Either the homeodomain or Pbx1 amino acids flanking this region could mediate transformation when fused to E2a. However, the homeodomain was not essential for transformation, since a mutant E2a-Pbx1 protein (E2a-Pbx delta HD) lacking the homeodomain efficiently transformed fibroblasts and induced malignant lymphomas in transgenic mice. Thus, transformation mediated by the chimeric oncoprotein E2a-Pbx1 is absolutely dependent on motifs acquired from E2a but the Pbx1 homeodomain is optional. The latter finding suggests that E2a-Pbx1 may interact with cellular proteins that assist or mediate alterations in gene expression responsible for oncogenesis even in the absence of homeodomain-DNA interactions.

scholarly journals Strigolactone promotes cytokinin degradation through transcriptional activation ofCYTOKININ OXIDASE/DEHYDROGENASE 9in rice

2019 ◽  
Vol 116 (28) ◽  
pp. 14319-14324 ◽  
Author(s):  
Jingbo Duan ◽  
Hong Yu ◽  
Kun Yuan ◽  
Zhigang Liao ◽  
Xiangbing Meng ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Plant Hormone ◽  
Response Regulator ◽  
Critical Role ◽  
Primary Response ◽  
Cytokinin Oxidase ◽  
Wild Type ◽  
Shoot Architecture ◽  
In The Wild ◽  
F Box Protein

Strigolactones (SLs), a group of terpenoid lactones derived from carotenoids, are plant hormones that control numerous aspects of plant development. Although the framework of SL signaling that the repressor DWARF 53 (D53) could be SL-dependently degraded via the SL receptor D14 and F-box protein D3 has been established, the downstream response genes to SLs remain to be elucidated. Here we show that the cytokinin (CK) content is dramatically increased in shoot bases of the rice SL signaling mutantd53. By examining transcript levels of all the CK metabolism-related genes after treatment with SL analog GR24, we identifiedCYTOKININ OXIDASE/DEHYDROGENASE 9(OsCKX9) as a primary response gene significantly up-regulated within 1 h of treatment in the wild type but not ind53. We also found that OsCKX9 functions as a cytosolic and nuclear dual-localized CK catabolic enzyme, and that the overexpression ofOsCKX9suppresses the browning ofd53calli. Both the CRISPR/Cas9-generatedOsCKX9mutants andOsCKX9-overexpressing transgenic plants showed significant increases in tiller number and decreases in plant height and panicle size, suggesting that the homeostasis ofOsCKX9plays a critical role in regulating rice shoot architecture. Moreover, we identified the CK-inducible rice type-A response regulatorOsRR5as the secondary SL-responsive gene, whose expression is significantly repressed after 4 h of GR24 treatment in the wild type but not inosckx9. These findings reveal a comprehensive plant hormone cross-talk in which SL can induce the expression ofOsCKX9to down-regulate CK content, which in turn triggers the response of downstream genes.

Ozone-induced lung inflammation and hyperreactivity are mediated via tumor necrosis factor-α receptors

2001 ◽  
Vol 280 (3) ◽  
pp. L537-L546 ◽  
Author(s):  
Hye-Youn Cho ◽  
Liu-Yi Zhang ◽  
Steven R. Kleeberger
Keyword(s):  
Tumor Necrosis Factor ◽  
Lung Inflammation ◽  
Tumor Necrosis ◽  
Critical Role ◽  
Airway Hyperreactivity ◽  
Tnf Receptor ◽  
Wild Type ◽  
Targeted Disruption ◽  
Factor Α ◽  
Necrosis Factor

This study was designed to investigate the mechanisms through which tumor necrosis factor ( Tnf) modulates ozone (O3)-induced pulmonary injury in susceptible C57BL/6J (B6) mice. B6 [wild-type ( wt)] mice and B6 mice with targeted disruption (knockout) of the genes for the p55 TNF receptor [ TNFR1(−/−)], the p75 TNF receptor [ TNFR2(−/−)], or both receptors [ TNFR1/TNFR2(−/−)] were exposed to 0.3 parts/million O3 for 48 h (subacute), and lung responses were determined by bronchoalveolar lavage. All TNFR(−/−) mice had significantly less O3-induced inflammation and epithelial damage but not lung hyperpermeability than wt mice. Compared with air-exposed control mice, O3 elicited upregulation of lung TNFR1 and TNFR2 mRNAs in wt mice and downregulated TNFR1 and TNFR2 mRNAs in TNFR2(−/−) and TNFR1(−/−) mice, respectively. Airway hyperreactivity induced by acute O3 exposure (2 parts/million for 3 h) was diminished in knockout mice compared with that in wtmice, although lung inflammation and permeability remained elevated. Results suggested a critical role for TNFR signaling in subacute O3-induced pulmonary epithelial injury and inflammation and in acute O3-induced airway hyperreactivity.

scholarly journals Amino Acid Residues in LuxR Critical for Its Mechanism of Transcriptional Activation during Quorum Sensing inVibrio fischeri

2001 ◽  
Vol 183 (1) ◽  
pp. 387-392 ◽  
Author(s):  
Amy E. Trott ◽  
Ann M. Stevens
Keyword(s):  
Amino Acid ◽  
Dna Binding ◽  
Quorum Sensing ◽  
Transcriptional Activation ◽  
Transcription Initiation ◽  
Critical Role ◽  
Site Directed Mutagenesis ◽  
Amino Acid Residues ◽  
Wild Type

ABSTRACT PCR-based site-directed mutagenesis has been used to generate 38 alanine-substitution mutations in the C-terminal 41 amino acid residues of LuxR. This region plays a critical role in the mechanism of LuxR-dependent transcriptional activation of the Vibrio fischeri lux operon during quorum sensing. The ability of the variant forms of LuxR to activate transcription of the lux operon was examined by using in vivo assays in recombinant Escherichia coli. Eight recombinant strains produced luciferase at levels less than 50% of that of a strain expressing wild-type LuxR. Western immunoblotting analysis verified that the altered forms of LuxR were expressed at levels equivalent to those of the wild type. An in vivo DNA binding-repression assay in recombinant E. coli was subsequently used to measure the ability of the variant forms of LuxR to bind to the lux box, the binding site of LuxR at thelux operon promoter. All eight LuxR variants found to affect cellular luciferase levels were unable to bind to thelux box. An additional 11 constructs that had no effect on cellular luciferase levels were also found to exhibit a defect in DNA binding. None of the alanine substitutions in LuxR affected activation of transcription of the lux operon without also affecting DNA binding. These results support the conclusion that the C-terminal 41 amino acids of LuxR are important for DNA recognition and binding of the lux box rather than positive control of the process of transcription initiation.

scholarly journals The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Dong-Hyun Kim ◽  
Jung Sun Park ◽  
Hoon-In Choi ◽  
Chang Seong Kim ◽  
Eun Hui Bae ◽  
...  
Keyword(s):  
Critical Role ◽  
Kidney Injury ◽  
Farnesoid X Receptor ◽  
Wild Type ◽  
Expression Levels ◽  
Related Proteins ◽  
Hk2 Cells ◽  
Oxidative Species ◽  
Feeding And Fasting

AbstractAutophagy is important for cells to break down and recycle cellular proteins, remove damaged organelles, and especially, for recovery from acute kidney injury (AKI). Despite research on the role and cellular mechanism of autophagy in AKI, the role of autophagy in the progression to chronic kidney disease (CKD) remains poorly understood. Here, using farnesoid X receptor (FXR) knockout (KO) mice, we determined whether FXR prevents the progression of AKI to CKD after renal ischemic-reperfusion (such as I/R) injury through the regulation of renal autophagy and apoptosis. FXR regulated genes that participate in renal autophagy under feeding and fasting conditions, such as hepatic autophagy, and the activation of FXR by agonists, such as GW4064 and INT-747, attenuated the increased autophagy and apoptosis of hypoxia-induced human renal proximal tubule epithelial (HK2) cells. The expression levels of autophagy-related and apoptosis-related proteins in FXR KO mice were increased compared with those in wild-type (WT) mice. We also showed that the increase in reactive oxidative species (ROS) in hypoxia-treated HK2 cells was attenuated by treatment with FXR agonist or by FXR overexpression, and that the level of ROS was elevated in FXR-deficient cells and mice. At 28 days after I/R injury, the autophagy levels were still elevated in FXR KO mice, and the expression levels of fibrosis-related proteins and ROS deposits were higher than those in WT mice. In conclusion, the regulation of renal autophagy and apoptosis by FXR may be a therapeutic target for the early stages of kidney damage, and the progression of AKI to CKD.

scholarly journals Transcriptional Activation in Yeast Cells Lacking Transcription Factor IIA

Genetics ◽  
1999 ◽  
Vol 153 (4) ◽  
pp. 1573-1581 ◽  
Author(s):  
Susanna Chou ◽  
Sukalyan Chatterjee ◽  
Mark Lee ◽  
Kevin Struhl
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activation ◽  
Large Subunit ◽  
Yeast Cells ◽  
Specific Cell ◽  
Wild Type ◽  
Activation Domains ◽  
Cycle Arrest ◽  
General Transcription Factor

Abstract The general transcription factor IIA (TFIIA) forms a complex with TFIID at the TATA promoter element, and it inhibits the function of several negative regulators of the TATA-binding protein (TBP) subunit of TFIID. Biochemical experiments suggest that TFIIA is important in the response to transcriptional activators because activation domains can interact with TFIIA, increase recruitment of TFIID and TFIIA to the promoter, and promote isomerization of the TFIID-TFIIA-TATA complex. Here, we describe a double-shut-off approach to deplete yeast cells of Toa1, the large subunit of TFIIA, to <1% of the wild-type level. Interestingly, such TFIIA-depleted cells are essentially unaffected for activation by heat shock factor, Ace1, and Gal4-VP16. However, depletion of TFIIA causes a general two- to threefold decrease of transcription from most yeast promoters and a specific cell-cycle arrest at the G2-M boundary. These results indicate that transcriptional activation in vivo can occur in the absence of TFIIA.

scholarly journals The small protein MafG plays a critical role in MC3T3-E1 cell apoptosis induced by simulated microgravity and radiation

2021 ◽  
Vol 555 ◽  
pp. 175-181
Author(s):  
Honghui Wang ◽  
Jingjing Dong ◽  
Gaozhi Li ◽  
Yingjun Tan ◽  
Hai Zhao ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Simulated Microgravity ◽  
Critical Role ◽  
Small Protein

scholarly journals 1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer

2021 ◽  
Vol 7 (4) ◽  
pp. eabe1174
Author(s):  
Marisa K. Kilgour ◽  
Sarah MacPherson ◽  
Lauren G. Zacharias ◽  
Abigail E. Ellis ◽  
Ryan D. Sheldon ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Modulation ◽  
Human Cancer ◽  
Serous Carcinoma ◽  
Necrosis Factor Alpha ◽  
Methyl Group ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Alpha ◽  
Immunotherapy Target ◽  
Necrosis Factor

Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few exceptions, their identities remain largely unknown. Here, we profiled tumor and T cells from tumor and ascites of patients with high-grade serous carcinoma (HGSC) to uncover the metabolomes of these distinct TME compartments. Cells within the ascites and tumor had pervasive metabolite differences, with a notable enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared with ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the enzyme that catalyzes the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Functionally, MNA induces T cells to secrete the tumor-promoting cytokine tumor necrosis factor alpha. Thus, TME-derived MNA contributes to the immune modulation of T cells and represents a potential immunotherapy target to treat human cancer.

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