The Drosophila dCREB-A gene is required for dorsal/ventral patterning of the larval cuticle

Development ◽  
1997 ◽  
Vol 124 (1) ◽  
pp. 181-193 ◽  
Author(s):  
D.J. Andrew ◽  
A. Baig ◽  
P. Bhanot ◽  
S.M. Smolik ◽  
K.D. Henderson
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Signaling Cascades ◽  
Loss Of Function ◽  
Larval Cuticle ◽  
Extracellular Signals ◽  
Patterning Genes ◽  
Lateral Structures ◽  
Cuticular Structures

We report on the characterization of the first loss-of-function mutation in a Drosophila CREB gene, dCREB-A. In the epidermis, dCREB-A is required for patterning cuticular structures on both dorsal and ventral surfaces since dCREB-A mutant larvae have only lateral structures around the entire circumference of each segment. Based on results from epistasis tests with known dorsal/ventral patterning genes, we propose that dCREB-A encodes a transcription factor that functions near the end of both the DPP- and SPI-signaling cascades to translate the corresponding extracellular signals into changes in gene expression. The lateralizing phenotype of dCREB-A mutants reveals a much broader function for CREB proteins than previously thought.

scholarly journals Endolysosomal Cation Channels and MITF in Melanocytes and Melanoma

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1021
Author(s):  
Carla Abrahamian ◽  
Christian Grimm
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcription Factor ◽  
Convincing Evidence ◽  
Signaling Cascades ◽  
Cation Channels ◽  
Pore Channel ◽  
Different Types ◽  
Canonical Wnt ◽  
The Relationship

Microphthalmia-associated transcription factor (MITF) is the principal transcription factor regulating pivotal processes in melanoma cell development, growth, survival, proliferation, differentiation and invasion. In recent years, convincing evidence has been provided attesting key roles of endolysosomal cation channels, specifically TPCs and TRPMLs, in cancer, including breast cancer, glioblastoma, bladder cancer, hepatocellular carcinoma and melanoma. In this review, we provide a gene expression profile of these channels in different types of cancers and decipher their roles, in particular the roles of two-pore channel 2 (TPC2) and TRPML1 in melanocytes and melanoma. We specifically discuss the signaling cascades regulating MITF and the relationship between endolysosomal cation channels, MAPK, canonical Wnt/GSK3 pathways and MITF.

scholarly journals Genomic Characterization of Endothelial Enhancers Reveals a Multifunctional Role for NR2F2 in Regulation of Arteriovenous Gene Expression

2020 ◽  
Vol 126 (7) ◽  
pp. 875-888 ◽  
Author(s):  
Samir Sissaoui ◽  
Jun Yu ◽  
Aimin Yan ◽  
Rui Li ◽  
Onur Yukselen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Transcription Factor ◽  
Deep Sequencing ◽  
Chromatin Immunoprecipitation ◽  
Regulatory Elements ◽  
Bhlh Transcription Factor ◽  
Genome Wide ◽  
A Genome

Rationale: Significant progress has revealed transcriptional inputs that underlie regulation of artery and vein endothelial cell fates. However, little is known concerning genome-wide regulation of this process. Therefore, such studies are warranted to address this gap. Objective: To identify and characterize artery- and vein-specific endothelial enhancers in the human genome, thereby gaining insights into mechanisms by which blood vessel identity is regulated. Methods and Results: Using chromatin immunoprecipitation and deep sequencing for markers of active chromatin in human arterial and venous endothelial cells, we identified several thousand artery- and vein-specific regulatory elements. Computational analysis revealed that NR2F2 (nuclear receptor subfamily 2, group F, member 2) sites were overrepresented in vein-specific enhancers, suggesting a direct role in promoting vein identity. Subsequent integration of chromatin immunoprecipitation and deep sequencing data sets with RNA sequencing revealed that NR2F2 regulated 3 distinct aspects related to arteriovenous identity. First, consistent with previous genetic observations, NR2F2 directly activated enhancer elements flanking cell cycle genes to drive their expression. Second, NR2F2 was essential to directly activate vein-specific enhancers and their associated genes. Our genomic approach further revealed that NR2F2 acts with ERG (ETS-related gene) at many of these sites to drive vein-specific gene expression. Finally, NR2F2 directly repressed only a small number of artery enhancers in venous cells to prevent their activation, including a distal element upstream of the artery-specific transcription factor, HEY2 (hes related family bHLH transcription factor with YRPW motif 2). In arterial endothelial cells, this enhancer was normally bound by ERG, which was also required for arterial HEY2 expression. By contrast, in venous endothelial cells, NR2F2 was bound to this site, together with ERG, and prevented its activation. Conclusions: By leveraging a genome-wide approach, we revealed mechanistic insights into how NR2F2 functions in multiple roles to maintain venous identity. Importantly, characterization of its role at a crucial artery enhancer upstream of HEY2 established a novel mechanism by which artery-specific expression can be achieved.

scholarly journals The Rab5-Rab11 endosomal pathway is required for BDNF-induced CREB transcriptional regulation in neurons

2019 ◽  
Author(s):  
Andrés G. González ◽  
Oscar M. Lazo ◽  
Francisca C. Bronfman
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Plasma Membrane ◽  
Neurotrophic Factor ◽  
Dendritic Growth ◽  
Signaling Cascades ◽  
Transcriptional Responses ◽  
Recycling Endosomes ◽  
Central Neurons ◽  
Endosomal Pathway

AbstractBrain-derived neurotrophic factor (BDNF) is a key regulator of the morphology and connectivity of central neurons. We have previously shown that BDNF/TrkB signaling regulates the activity and mobility of the GTPases Rab5 and Rab11, which in turn determine the post-endocytic sorting of signaling TrkB receptors. Moreover, altered Rab5 or Rab11 activity inhibits BDNF-induced dendritic branching. Whether Rab5 or Rab11 activity is important for local events only, or also for regulating nuclear signaling and gene expression, is unknown. Here, we investigated whether BDNF-induced signaling cascades were altered when early and recycling endosomes were disrupted by the expression of dominant negative mutants of Rab5 and Rab11. The activities of both Rab5 and Rab11 were required for sustained activity of Erk1/2 and nuclear CREB phosphorylation and for increased transcription of BDNF-dependent genes containing CRE-binding sites that include activity-regulated genes such as Arc, Dusp1, c-fos and Egr1 and growth and survival genes such as Atf3 and Nf1. Based on our results, we propose that the early and recycling endosomes provide a platform for the integration of neurotrophic signaling from the plasma membrane to the nucleus in neurons and that this mechanism likely regulates neuronal plasticity and neuronal survival.Significance StatementBDNF is a soluble neurotrophic factor that regulates plastic changes in the brain, including dendritic growth, by binding to its plasma membrane receptor TrkB. BDNF/TrkB activates signaling cascades leading to activation of CREB, a key transcription factor regulating circuit development and learning and memory. Our results uncover the cellular mechanisms that central neurons use to integrate the signaling of plasma membrane receptors with nuclear transcriptional responses. We found that the endosomal pathway is required for the signaling cascade initiated by BDNF and its receptors in the plasma membranes to modulate BDNF-dependent gene expression and neuronal dendritic growth mediated by the CREB transcription factor in the nucleus.

scholarly journals Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM)

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 7
Author(s):  
Moshe Lapidot ◽  
Abigail E. Case ◽  
Dalia Larios ◽  
Helen I. Gandler ◽  
Chengcheng Meng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Transcription Factor ◽  
Cell Growth ◽  
Malignant Pleural Mesothelioma ◽  
Cell Cycle Progression ◽  
Pleural Mesothelioma ◽  
Loss Of Function ◽  
P53 Response

Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression, using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response, including upregulation of ICOSLG (Inducible T-Cell Costimulator Ligand or B7H2). Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics.

scholarly journals Structural characterization of the ternary complex that mediates termination of NF-κB signaling by IκBα

2016 ◽  
Vol 113 (22) ◽  
pp. 6212-6217 ◽  
Author(s):  
Sulakshana P. Mukherjee ◽  
Pedro O. Quintas ◽  
Reginald McNulty ◽  
Elizabeth A. Komives ◽  
H. Jane Dyson
Keyword(s):  
Transcription Factor ◽  
Dna Sequence ◽  
Ternary Complex ◽  
Kinetic Studies ◽  
Structural Data ◽  
Structural Basis ◽  
Extracellular Signals ◽  
Negative Stain ◽  
Modeled Structure

The transcription factor NF-κB is used in many systems for the transduction of extracellular signals into the expression of signal-responsive genes. Published structural data explain the activation of NF-κB through degradation of its dedicated inhibitor IκBα, but the mechanism by which NF-κB–mediated signaling is turned off by its removal from the DNA in the presence of newly synthesized IκBα (termed stripping) is unknown. Previous kinetic studies showed that IκBα accelerates NF-κB dissociation from DNA, and a transient ternary complex between NF-κB, its cognate DNA sequence, and IκBα was observed. Here we structurally characterize the >100-kDa ternary complex by NMR and negative stain EM and show a modeled structure that is consistent with the measurements. These data provide a structural basis for previously unidentified insights into the molecular mechanism of stripping.

scholarly journals Treating a Dysregulated JAK/STAT Pathway in Cancer Cells

2016 ◽  
Vol 5 (1) ◽  
pp. 11-17
Author(s):  
Jarod M. Schieler ◽  
Jeffrey O. Henderson
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Tumor Suppressor Genes ◽  
Stat Proteins ◽  
Extracellular Signals ◽  
Cognate Receptor ◽  
Response Differentiation ◽  
Proliferation And Apoptosis ◽  
Stat Pathway

The JAK/STAT pathway is induced by the binding of a cytokine to its cognate receptor. The receptor’s engagement with the cytokine recruits a JAK protein, which activates itself via auto/trans-phosphorylation. In turn, the activated JAKs recruit and phosphorylate STAT proteins. The phosphorylated STAT proteins form a dimer, translocate to the cell nucleus and acts as a transcription factor to induce gene expression. In this way, the JAK/STAT pathway can mediate a cell’s response to extracellular signals. The proteins ultimately induced by the JAK/STAT pathway contribute to processes such as inflammatory response, differentiation, proliferation, and apoptosis. When the JAK/STAT pathway becomes dysregulated, proto-oncogenes and/or tumor-suppressor genes are often inappropriately expressed, commonly resulting in oncogenesis. This review discusses how SOCS, PIAS, and PTPS proteins modulate the JAK/STAT pathway ensuring that it remains cyclic and transient.  The use of jakibins, STAT inhibitors, decoy oligonucleotides, RNA interference and genome editing to synthetically regulate a dysregulated JAK/STAT pathway in cancer cells are also considered.

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