scholarly journals What turns CREB on? And off? And why does it matter?

2020 ◽  
Vol 77 (20) ◽  
pp. 4049-4067 ◽  
Author(s):  
André Steven ◽  
Michael Friedrich ◽  
Paul Jank ◽  
Nadine Heimer ◽  
Jan Budczies ◽  
...  
Keyword(s):  
Overall Survival ◽  
Transcription Factor ◽  
Cyclic Amp ◽  
Therapeutic Target ◽  
Therapy Response ◽  
Predictive Marker ◽  
Tumor Patients ◽  
Altered Expression ◽  
Underlying Mechanisms ◽  
And Function

Abstract Altered expression and function of the transcription factor cyclic AMP response-binding protein (CREB) has been identified to play an important role in cancer and is associated with the overall survival and therapy response of tumor patients. This review focuses on the expression and activation of CREB under physiologic conditions and in tumors of distinct origin as well as the underlying mechanisms of CREB regulation by diverse stimuli and inhibitors. In addition, the clinical relevance of CREB is summarized, including its use as a prognostic and/or predictive marker as well as a therapeutic target.

scholarly journals Screening and Authentication of Key Genes and Prognostic Value Analysis in Oligodendroglial Tumors

2020 ◽  
Author(s):  
Zhonghua Lv ◽  
Bongbo Bao ◽  
Peng Liang
Keyword(s):  
Overall Survival ◽  
Expression Profiles ◽  
Ppi Network ◽  
Hub Genes ◽  
Tumor Patients ◽  
Altered Expression ◽  
Oligodendroglial Tumor ◽  
Tumor Tissues ◽  
Key Genes ◽  
Tumor Pathogenesis

Abstract Background: Emerging evidence indicates that various functional genes with altered expression are involved in the human tumor progression. This study is aimed at identifying novel key genes that may be used for oligodendroglial tumor diagnosis, prognosis, and targeted therapy. Methods: This study included three expression profiles (GSE15824, GSE29796 and GSE108474) obtained from the Gene Expression Omnibus (GEO). GEO2R was used to analyze the differentially expressed genes (DEGs) between normal samples and oligodendroglial tumor, including oligodendroglioma and anaplastic oligodendroglioma. The functional and pathway enrichment analysis was performed by the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network of the identified DEGs was constructed using the Search Tool for the Retrieval of Interacting Gene, and hub genes were identified. ONCOMINE and The Cancer Genome Atlas (TCGA) databases were used to verify the expression of the hub genes in oligodendroglial tumor tissues and the hub genes on the overall survival of oligodendroglial tumor patients. Results: A total of 128 DEGs were identified from the three expression profiles. These DEGs were enriched with functional processes and pathways related to oligodendroglial tumor pathogenesis. From the PPI network, five hub genes were identified. The expression of the five hub genes was all upregulated in oligodendroglial tumor tissues compared with the control tissues. Kaplan-Meier survival curves indicated that high expression of cullin 3 (CUL3), cop9 signalosome subunit 8 (COPS8), cullin associated and neddylation dissociated 1 (CAND1), F-box protein 22 (FBXO22), and leucine rich repeat containing 41 (LRRC41) predicted poor overall survival in oligodendroglial tumor patients (all log-rank P < 0.01). Conclusions: These results revealed that the DEGs may serve as candidate key genes during oligodendroglial tumor pathogenesis. The five hub genes, including CUL3, COPS8, CAND1, FBXO22, and LRRC41, may serve as promising prognostic biomarkers in oligodendroglial tumor.

Integration of TMB and tumor heterogeneity identify an immunologic subtype of melanoma with favorable survival.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15183-e15183
Author(s):  
Chunhe Yang ◽  
Guodong Zhao ◽  
Jianfei Wang ◽  
Lingyu Wang ◽  
Ge Jin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Heterogeneity ◽  
Therapy Response ◽  
Predictive Marker ◽  
Checkpoint Inhibition ◽  
R Software ◽  
Mutational Burden ◽  
Superior Efficacy ◽  
Tumor Mutational Burden ◽  
Melanoma Patients

e15183 Background: Tumor mutational burden (TMB) has been reported a predictive marker of response to immune checkpoint inhibition (ICI) therapy in previous clinical trials. However, TMB alone is not sufficient to accurately predict immunotherapy benefit. Additional biomarkers are needed for better stratification of immunotherapy sensitive patients. Methods: Here we combined TMB with tumor heterogeneity for evaluating response to ICI treatment. Mutation and clinical data were collected from several melanoma immunotherapy studies, including cohort treated with Ipilimumab and anti-PD-(L)1/anti-CTLA-4 (VanAllen_2015, n = 110; Miao_2018, n = 151) and a cohort treated with Nivolumab (Riaz_2017, n = 60). Tumor heterogeneity was estimated with mutant-allele tumor heterogeneity (MATH) or clone number. Benefit score was defined as ratio between TMB and tumor heterogeneity and the most significant critical values were selected to group patients. Besides, we calculated clonal TMB and investigated its correlation with TMB and tumor heterogeneity. Statistical analyses were performed using R software. Results: Benefit score was tested in several cohorts as a marker of ICI therapy response. In VanAllen_2015 and Miao_2018 cohort, TMB/MATH score significantly improved the performance of stratifying the overall survival (OS) of patients with ICI treatment compared with TMB alone as predictor (p = 0.0068 vs. p = 0.1 and p = 0.028 vs. p = 0.042). In Riaz_2017 cohort, we used clone number to calculate the benefit score due to the unavailability of the raw data. In this cohort, benefit score is also positively associated with higher overall survival (p = 0.056), which outperforms TMB alone with a significance of p = 0.57. Moreover, clonal TMB showed positive correlation with TMB (R > 0.3) and negative correlation with tumor heterogeneity (R < -0.3) in one melanoma cohort (Miao_2018). Conclusions: Tumor heterogeneity, combined with TMB showed superior efficacy in predicting response of ICI therapy. This may further help delineating the mechanisms of immunotherapy in melanoma patients.

The Effect of Mitomycin C on Platelet Aggregation and Adenosine 3′, 5′-Monophosphate Metabolism

1978 ◽  
Vol 39 (01) ◽  
pp. 177-185 ◽  
Author(s):  
Shuichi Hashimoto ◽  
Sachiko Shibata ◽  
Bonro Kobayashi
Keyword(s):  
Platelet Aggregation ◽  
Cyclic Amp ◽  
Mitomycin C ◽  
Blood Platelets ◽  
Adenosine Diphosphate ◽  
Cellular Membrane ◽  
Adenyl Cyclase ◽  
Cyclic Amp Phosphodiesterase ◽  
Membrane Structure And Function ◽  
And Function

SummaryThe effect of Mitomycin C on aggregation, adenosine 3′, 5′-monophosphate (cyclic AMP) metabolism and reactions induced by thrombin was studied in rabbit platelets. Mitomycin C inhibited the platelet aggregation induced by adenosine diphosphate or thrombin. The level of radioactive cyclic AMP derived from 8-14C adenine or 8-14C adenosine increased after incubating intact platelets with Mitomycin G. Formation of radioactive adenosine triphosphate also increased though mitochondrial oxidation was not stimulated. Similar effect was observed also in rabbit liver. Mitomycin C failed to stimulate platelet adenyl cyclase but inhibited cyclic AMP phosphodiesterase in the absence of theophylline. In the platelets preincubated with Mitomycin C, thrombin-induced inhibition of adenyl cyclase, stimulation of membrane-bound cyclic AMP phosphodiesterase, and release of 250,000 dalton protein from platelet membranes were prevented. These results suggest that Mitomycin C will affect cellular membrane structure and function, and this extranuclear effect of Mitomycin C will lead to inhibition of aggregation in blood platelets.

scholarly journals Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function

Cell Reports ◽  
2021 ◽  
Vol 36 (4) ◽  
pp. 109446
Author(s):  
Benjamin Bourgeois ◽  
Tianshu Gui ◽  
Diana Hoogeboom ◽  
Henry G. Hocking ◽  
Gesa Richter ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factor Binding ◽  
Factor Binding ◽  
Intrinsically Disordered ◽  
And Function

scholarly journals Brassinosteroids repress the seed maturation program during the seed-to-seedling transition

2021 ◽  
Author(s):  
Jiuxiao Ruan ◽  
Huhui Chen ◽  
Tao Zhu ◽  
Yaoguang Yu ◽  
Yawen Lei ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Transcription Factor ◽  
Abscisic Acid ◽  
Plant Hormone ◽  
Flowering Plants ◽  
Seed Maturation ◽  
Domain Protein ◽  
Abscisic Acid Insensitive3 ◽  
Underlying Mechanisms ◽  
Embryonic Structure

Abstract In flowering plants, repression of the seed maturation program is essential for the transition from the seed to the vegetative phase, but the underlying mechanisms remain poorly understood. The B3-domain protein VIVIPAROUS1/ABSCISIC ACID-INSENSITIVE3-LIKE 1 (VAL1) is involved in repressing the seed maturation program. Here we uncovered a molecular network triggered by the plant hormone brassinosteroid (BR) that inhibits the seed maturation program during the seed-to-seedling transition in Arabidopsis (Arabidopsis thaliana). val1-2 mutant seedlings treated with a BR biosynthesis inhibitor form embryonic structures, whereas BR signaling gain-of-function mutations rescue the embryonic structure trait. Furthermore, the BR-activated transcription factors BRI1-EMS-SUPPRESSOR 1 and BRASSINAZOLE-RESISTANT 1 bind directly to the promoter of AGAMOUS-LIKE15 (AGL15), which encodes a transcription factor involved in activating the seed maturation program, and suppress its expression. Genetic analysis indicated that BR signaling is epistatic to AGL15 and represses the seed maturation program by downregulating AGL15. Finally, we showed that the BR-mediated pathway functions synergistically with the VAL1/2-mediated pathway to ensure the full repression of the seed maturation program. Together, our work uncovered a mechanism underlying the suppression of the seed maturation program, shedding light on how BR promotes seedling growth.

scholarly journals Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 359
Author(s):  
Hsiang-Hao Chuang ◽  
Yen-Yi Zhen ◽  
Yu-Chen Tsai ◽  
Cheng-Hao Chuang ◽  
Ming-Shyan Huang ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tumor Suppressors ◽  
Protein Conformation ◽  
Genome Stability ◽  
Recent Progress ◽  
Multiple Roles ◽  
Cancer Development ◽  
Cancer Hallmarks ◽  
Underlying Mechanisms ◽  
And Function

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.

scholarly journals Cathepsin K: A Novel Diagnostic and Predictive Biomarker for Renal Tumors

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2441
Author(s):  
Anna Caliò ◽  
Matteo Brunelli ◽  
Stefano Gobbo ◽  
Pedram Argani ◽  
Enrico Munari ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Therapy Response ◽  
Cathepsin K ◽  
Mtor Inhibitors ◽  
Predictive Marker ◽  
Predictive Biomarker ◽  
Renal Tumors ◽  
Epithelioid Angiomyolipoma

Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a potential molecular target. Indeed, cathepsin K is a recognized diagnostic tool for the identification of TFE3/TFEB-rearranged renal cell carcinoma, TFEB-amplified renal cell carcinoma, and pure epithelioid PEComa/epithelioid angiomyolipoma. More recently, its expression has been observed in a subgroup of eosinophilic renal neoplasms molecularly characterized by TSC/mTOR gene mutations. Interestingly, both TSC mutations or TFE3 rearrangement have been reported in pure epithelioid PEComa/epithelioid angiomyolipoma. Therefore, cathepsin K seems to be a downstream marker of TFE3/TFEB rearrangement, TFEB amplification, and mTOR pathway activation. Given the established role of mTOR inhibitors as a pharmacological option in renal cancers, cathepsin K could be of use as a predictive marker of therapy response and as a potential target. In the future, uropathologists may implement the use of cathepsin K to establish a diagnosis among renal tumors with clear cells, papillary architecture, and oncocytic features.

scholarly journals Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review

2021 ◽  
Vol 22 (9) ◽  
pp. 4955
Author(s):  
Guadalupe Rosario Fajardo-Orduña ◽  
Edgar Ledesma-Martínez ◽  
Itzen Aguiñiga-Sánchez ◽  
María de Lourdes Mora-García ◽  
Benny Weiss-Steider ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Acquired Resistance ◽  
Clonal Expansion ◽  
Leukemic Cells ◽  
Hematopoietic Progenitor ◽  
Primary Resistance ◽  
Altered Expression ◽  
Synergistic Cytotoxicity ◽  
And Function

Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation. Approximately 60% of AML patients respond favorably to these treatments and go into complete remission; however, most eventually relapse, develop refractory disease or chemoresistance, and do not survive for more than five years. Therefore, drug resistance that initially occurs in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) has become the main obstacle to AML treatment. In this work, the main molecules responsible for generating chemoresistance to Ara-C in AML are discussed, as well as some of the newer strategies to overcome it, such as the inclusion of molecules that can induce synergistic cytotoxicity with Ara-C (MNKI-8e, emodin, metformin and niclosamide), subtoxic concentrations of chemotherapy (PD0332991), and potently antineoplastic treatments that do not damage nonmalignant cells (heteronemin or hydroxyurea + azidothymidine).

scholarly journals Metabolome and proteome analyses reveal transcriptional misregulation in glycolysis of engineered E. coli

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chun-Ying Wang ◽  
Martin Lempp ◽  
Niklas Farke ◽  
Stefano Donati ◽  
Timo Glatter ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Site ◽  
Metabolic Pathways ◽  
Glycerol Production ◽  
Inducible Promoters ◽  
E Coli ◽  
Inhibition Of Glycolysis ◽  
Underlying Mechanisms ◽  
Rate Limiting ◽  
Engineered Bacteria

AbstractSynthetic metabolic pathways are a burden for engineered bacteria, but the underlying mechanisms often remain elusive. Here we show that the misregulated activity of the transcription factor Cra is responsible for the growth burden of glycerol overproducing E. coli. Glycerol production decreases the concentration of fructose-1,6-bisphoshate (FBP), which then activates Cra resulting in the downregulation of glycolytic enzymes and upregulation of gluconeogenesis enzymes. Because cells grow on glucose, the improper activation of gluconeogenesis and the concomitant inhibition of glycolysis likely impairs growth at higher induction of the glycerol pathway. We solve this misregulation by engineering a Cra-binding site in the promoter controlling the expression of the rate limiting enzyme of the glycerol pathway to maintain FBP levels sufficiently high. We show the broad applicability of this approach by engineering Cra-dependent regulation into a set of constitutive and inducible promoters, and use one of them to overproduce carotenoids in E. coli.

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