scholarly journals Targeting of NF-κB to Dendritic Spines is Required for Synaptic Signaling and Spine Development

2018 ◽  
Author(s):  
Erica C. Dresselhaus ◽  
Matthew C.H. Boersma ◽  
Mollie K. Meffert
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dendritic Spines ◽  
Brain Plasticity ◽  
Spatial Localization ◽  
Synaptic Activity ◽  
Wild Type ◽  
Spine Development ◽  
Response Expression ◽  
Activity Dependent

ABSTRACTLong-term forms of brain plasticity share a requirement for changes in gene expression induced by neuronal activity. Mechanisms that determine how the distinct and overlapping functions of multiple activity-responsive transcription factors, including nuclear factor kappa B (NF-κB), give rise to stimulus-appropriate neuronal responses remain unclear. We report that the p65/RelA subunit of NF-κB confers subcellular enrichment at neuronal dendritic spines and engineer a p65 mutant that lacks spine-enrichment (ΔSEp65) but retains inherent transcriptional activity equivalent to wild-type p65. Wild-type p65 or ΔSEp65 both rescue NF-κB-dependent gene expression in p65-deficient murine hippocampal neurons responding to diffuse (PMA/ionomycin) stimulation. In contrast, neurons lacking spine-enriched NF-κB are selectively impaired in NF-κB-dependent gene expression induced by elevated excitatory synaptic stimulation (bicuculline or glycine). We used the setting of excitatory synaptic activity during development that produces NF-κB-dependent growth of dendritic spines to test physiological function of spine-enriched NF-κB in an activity-dependent response. Expression of wild-type p65, but not ΔSEp65, is capable of rescuing spine density to normal levels in p65-deficient pyramidal neurons. Collectively, these data reveal that spatial localization in dendritic spines contributes unique capacities to the NF-κB transcription factor in synaptic activity-dependent responses.SIGNIFICANCE STATEMENTExtensive research has established a model in which the regulation of neuronal gene expression enables enduring forms of plasticity and learning. However, mechanisms imparting stimulus-specificity to gene regulation, insuring biologically appropriate responses, remain incompletely understood. NF-κB is a potent transcription factor with evolutionarily-conserved functions in learning and the growth of excitatory synaptic contacts. Neuronal NF-κB is localized in both synapse and somatic compartments, but whether the synaptic pool of NF-κB has discrete functions is unknown. This study reveals that NF-κB enriched in dendritic spines (the postsynaptic sites of excitatory contacts) is selectively required for NF-κB activation by synaptic stimulation and normal dendritic spine development. These results support spatial localization at synapses as a key variable mediating selective stimulus-response coupling.

scholarly journals The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ian Edward Gentle ◽  
Isabel Moelter ◽  
Mohamed Tarek Badr ◽  
Konstanze Döhner ◽  
Michael Lübbert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Wild Type ◽  
Elevated Expression ◽  
Factor C ◽  
Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

Role of heat shock transcription factor in yeast metallothionein gene expression

1991 ◽  
Vol 11 (7) ◽  
pp. 3676-3681
Author(s):  
W M Yang ◽  
W Gahl ◽  
D Hamer
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Heat Shock ◽  
Gene Transcription ◽  
Heat Shock Factor ◽  
Heat Shock Transcription Factor ◽  
Wild Type ◽  
Promoter Sequences ◽  
Metallothionein Gene ◽  
Upstream Promoter

The induction of Saccharomyces cerevisiae metallothionein gene transcription by Cu and Ag is mediated by the ACE1 transcription factor. In an effort to detect additional stimuli and factors that regulate metallothionein gene transcription, we isolated a Cu-resistant suppressor mutant of an ACE1 deletion strain. Even in the absence of metals, the suppressor mutant exhibited high basal levels of metallothionein gene transcription that required upstream promoter sequences. The suppressor gene was cloned, and its predicted product was shown to correspond to yeast heat shock transcription factor with a single-amino-acid substitution in the DNA-binding domain. The mutant heat shock factor bound strongly to metallothionein gene upstream promoter sequences, whereas wild-type heat shock factor interacted weakly with the same region. Heat treatment led to a slight but reproducible induction of metallothionein gene expression in both wild-type and suppressor strains, and Cd induced transcription in the mutant strain. These studies provide evidence for multiple pathways of metallothionein gene transcriptional regulation in S. cerevisiae.

scholarly journals The temporal transcription factor E93 controls dynamic enhancer activity and chromatin accessibility during development

2019 ◽  
Author(s):  
Spencer L. Nystrom ◽  
Matthew J. Niederhuber ◽  
Daniel J. McKay
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Developmental Time ◽  
Chromatin Accessibility ◽  
Wild Type ◽  
Spatial Cues ◽  
Enhancer Activity ◽  
Temporal Gene Expression ◽  
Developmental Program ◽  
Temporal Cues

ABSTRACTHow temporal cues combine with spatial inputs to control gene expression during development is poorly understood. Here, we test the hypothesis that the Drosophila transcription factor E93 controls temporal gene expression by regulating chromatin accessibility. Precocious expression of E93 early in wing development reveals that it can simultaneously activate and deactivate different target enhancers. Notably, the precocious patterns of enhancer activity resemble the wild-type patterns that occur later in development, suggesting that provision of E93 alters the competence of enhancers to respond to spatial cues. Genomic profiling reveals that precocious E93 expression is sufficient to regulate chromatin accessibility at a subset of its targets. These accessibility changes mimic those that normally occur later in development, indicating that precocious E93 accelerates the wild-type developmental program. Further, we find that target enhancers that do not respond to precocious E93 in early wings become responsive after a developmental transition, suggesting that parallel temporal pathways work alongside E93. These findings support a model wherein E93 expression functions as an instructive cue that defines a broad window of developmental time through control of chromatin accessibility.

scholarly journals Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Philip Hasel ◽  
Owen Dando ◽  
Zoeb Jiwaji ◽  
Paul Baxter ◽  
Alison C. Todd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neuronal Activity ◽  
Cortical Neurons ◽  
Synaptic Activity ◽  
Rna Seq ◽  
Metabolic Cooperation ◽  
Closely Related Species ◽  
Lactate Shuttle ◽  
Activity Dependent ◽  
Elevated Lactate

Abstract The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte–neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte–neuron metabolic cooperation.

Disrupted co-ordination of Pax-8 and thyroid transcription factor-1 gene expression in a dedifferentiated rat thyroid tumour cell line derived from FRTL-5

1996 ◽  
Vol 150 (3) ◽  
pp. 377-382 ◽  
Author(s):  
C J H van der Kallen ◽  
D C J Spierings ◽  
J H H Thijssen ◽  
M A Blankenstein ◽  
T W A de Bruin
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Line ◽  
Thyroid Peroxidase ◽  
Wild Type ◽  
Specific Expression ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Rat Thyroid ◽  
Transcription Factor 1

Abstract The mutant rat thyroid cell line FRTL-5/TA, isolated from a non-functional tumour which originated spontaneously from wild-type FRTL-5 cells, shows autonomous TSH-independent growth and loss of the thyroid-specific phenotype, lacking thyroid-specific expression of thyroglobulin (Tg) and thyroid peroxidase (TPO) genes. To investigate the role of the transcription factors Pax-8 and thyroid transcription factor-1 (TTF-1) in rat thyroid tumorigenesis, RNA expression of these two thyroid-specific nuclear factors was measured in FRTL-5/TA tumour cells and compared with the expression in wild-type FRTL-5 cells. TTF-1 gene expression was similar to that in wild-type FRTL-5, and showed a similar down-regulation after stimulation with TSH. The finding suggested normal TTF-1 mRNA and protein expression in both cell lines. By contrast, Pax-8 mRNA transcript signal was markedly reduced in FRTL-5/TA cells, reaching levels as low as 8% of the normal, basal level in FRTL-5 cells. These data indicated that the loss of thyroid-specific expression of Tg and TPO genes in FRTL-5/TA cells was not related to changes in TTF-1 gene expression but rather to reduced Pax-8 gene expression. It was concluded that a disruption of the co-ordinated expression of TTF-1 and Pax-8 is implicated in the loss of thyroid phenotype of FRTL-5/TA cells in terms of reduced Tg and TPO expression. Journal of Endocrinology (1996) 150, 377–382

scholarly journals CEBPA Gene Mutations Interfere with Expressions of NKG2D Ligands Ulbps in AML Cells and Modulate Their Susceptibility to NK-Mediated Lysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1257-1257
Author(s):  
Meng Liu ◽  
Limengmeng Wang ◽  
Huafang Wang ◽  
Shan Fu ◽  
He Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Germ Line ◽  
Gene Expression Microarray ◽  
Wild Type ◽  
Expression Microarray ◽  
Over Expression ◽  
Microarray Profiling ◽  
Type C ◽  
Profiling Analysis

Introduction: CEBPA gene encodes CCAAT/enhancer-binding protein-alpha (C/EBPα), a crucial granulocytic differentiation factor and tumor suppressor in hematologic and many non-hematologic malignancies. We previously reported a donor-derived relapse of AML patient after allogeneic hematopoietic stem cell transplantation with multiple mutations in CEBPA gene: a N-terminal frameshift mutation (247dupC causing overproduction of truncated 30-KDa isoform, lacking the TAD1 domain, p30), a N-terminal germ-line mutation (584_589dup disrupting the TAD2 domain of protein, NM2), and a C-terminal mutation (914_916dup disrupting the bZIP domain, CM) (Blood 2011; 117: 5257-5260). Although studies from multiple laboratories have contributed immensely to our understanding that how different CEBPA mutations disturb C/EBPα functions including granulopoiesis and leukemic transformation in AML, whether C/EBPα might regulate immunosurveillance remains unknown. Methods: AML cell line cells infected with lentivirus to over-express of wild type C/EBPα as well as 3 types of C/EBPα mutants were co-cultured with NK92MI cells and detected cytotoxic lysis through FCM. NK92MI cells were stained with CD107a to detect degranulation.We performed gene expression microarray profiling analysis in AML cell line cells with over-expression of wild type C/EBPα and mutants . Flag tagged wide type C/EBPα was over-expressed in 293T cells and ChIP with anti-Flag antibody followed by sequencing assay was performed to explore candidate gene binding sites of C/EBPα. Finally, independent ChIP-qPCR of candidate sequences were performed to further verify the transcription factor binding sites of C/EBPα. Results: ULBPs expressed on the surface of tumor or infected cells are important ligands of NK cell receptor NKG2D. Our gene expression microarray profiling analysis showed that wild type C/EBPα could up-regulate the expression of ULBP2/5/6 in AML cell line cells. Consistent with the results of gene expression microarray profiling analysis, over-expression of wild type C/EBPα and a N-terminal germ-line mutant (NM2) can up-regulate ULBP2/5/6 expression in NB4 cells, whose endogenous expression of ULBPs was low. Meanwhile, the sensitivities of NB4 cells to the cytotoxicity of NK92MI cells were also increased by over-expression of wide type C/EBPα and NM2 mutant. In contrast, leukemia-associated somatic mutations, C/EBPα p30 and C-terminal mutant (CM), were disabled to up-regulate ULBPs expression. In dual-luciferase reporter assay, the ratio of level of firefly luciferase and renilla luciferase significantly increased when co-transduced report plasmid with wide type C/EBPα expressing plasmid compared with vector control, indicating that C/EBPα could up-regulate the transcription of ULBP2 as a transcription factor. Through ChIP-seq assay we identified 12 peaks nearby ULBP genes in chromosome 6. We further performed ChIP-qPCR to target the sequences acting as enhancers of ULBP genes, which located +7kb upstream of transcription start site of ULBP2 gene, +11kb upstream of ULBP5 gene, -9kb downstream of ULBP6 gene and -40kb downstream of ULBP1 gene. Wide type C/EBPα showed higher binding affinity to the ULBP2/5 enhancers with more than 50 folds' enrichment and to the ULBP6/1 enhancers 9 folds' enrichment compared with IgG control. The N-terminal germ-line mutant (NM2) conserved part of the binding affinity, but the enrich fold was lower than wide type. As expected, leukemia-associated C-terminal mutant (CM) totally lost its binding ability to both sequences due to the damage of DNA binding domain. Althoughleukemia-associated truncated 30-KDa isoform partly conserved its binding ability to these DNA sequences, the mutant lost the function of regulating ULBPs expression. Conclusions: C/EBPα played an important role in innate immunosurveillance of AML. C/EBPα could bind to the promoter and potential enhancers of ULBP genes as a transcription factor, up-regulate expression of ULBPs and eventually induce AML cells to be recognized and killed by NK cells. Mutations in TAD2 domain did not affect this regulation function, while mutations in TAD1 and bZIP domain lost the specific ability. Leukemia cells with N-terminal frameshift mutations (p30), or C-terminal mutations could escape from surveillance of NK cells and may play pivotal roles in leukemia relapse. Disclosures No relevant conflicts of interest to declare.

Translating Memories

2013 ◽  
Vol 6 (273) ◽  
pp. ec94-ec94 ◽  
Author(s):  
Nancy R. Gough
Keyword(s):  
Fear Conditioning ◽  
Hippocampal Slices ◽  
Contextual Fear Conditioning ◽  
Synaptic Activity ◽  
Wild Type ◽  
Conditioning Paradigm ◽  
Contextual Fear ◽  
Activity Dependent ◽  
New Protein

The cellular model of memory is a synaptic plasticity event called long-term potentiation (LTP). LTP can be divided into two phases: The early phase (E-LTP) lasts less than 2 hours and does not require new protein synthesis, and the late phase (L-LTP) can last many hours and requires new protein synthesis. Translation of mRNAs is regulated through various mechanisms, one of which is the binding of poly(A)-binding protein (PABP) to the poly(A) tail of the target mRNA. PAIP2A and PAIP2B (PAIP-interacting protein 2A and 2B) inhibit translation by interfering with PABP function. Khoutorsky et al. found that degradation of PAIP2A, which is the form that is abundant in the brain, linked synaptic activity to enhanced translation and contributed to learning and memory in mice. Hippocampal slices from Paip2a–/– mice showed L-LTP in response to a stimulus that only triggered E-LTP in slices from wild-type mice and showed impaired L-LTP in response to a stimulus that triggered L-LTP in slices from wild-type mice. Consistent with these electrophysiological studies, behavorial memory tests indicated that Paip2a–/– mice showed faster learning in spatial long-term memory tests in response to weak training but showed impaired learning in response to a long-term contextual fear conditioning test that used a strong training paradigm. Experiments with cultured neurons and hippocampal slices showed an activity-dependent decrease in the abundance of PAIP2A that could be prevented by pharmacological inhibition of the calcium-dependent proteases calpains. The calpain-dependent reduction in PAIP2A was also detected in mice subjected to the contextual fear conditioning paradigm, and infusion of calpain inhibitors impaired long-term contextual fear memory. Increased production of calcium-calmodulin kinase IIα (CaMKIIα) occurs in response to synaptic activity and is necessary for learning. The abundance of CaMKIIα in the hippocampus was increased in Paip2a–/– mice trained in a contextual fear conditioning paradigm compared with untrained mice or wild-type trained mice. This increase in CaMKIIα resulted from increased translation because CaMKIIα mRNA was shifted to heavy polysome fractions in the brains of Paip2a–/– trained mice and the association of PABP with this mRNA was greatest in the Paip2a–/– trained mice. Thus, activity-dependent degradation of a translation inhibitor contributes to the enhanced translation needed for learning and memory.A. Khoutorsky, A, Yanagiya, C. G. Gkogkas, M. R. Fabian, M. Prager-Khoutorsky, R. Cao, K. Gamache, F. Bouthiette, A. Parsyan, R. E. Sorge, J. S. Mogil, K. Nader, J.-C. Lacaille, N. Sonenberg, Control of synaptic plasticity and memory via suppression of poly(A)-binding protein. Neuron78, 298–311 (2013). [Online Journal]

scholarly journals Crm1-Mediated Nuclear Export of the Schizosaccharomyces pombe Transcription Factor Cuf1 during a Shift from Low to High Copper Concentrations

2007 ◽  
Vol 6 (5) ◽  
pp. 764-775 ◽  
Author(s):  
Jude Beaudoin ◽  
Simon Labbé
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Schizosaccharomyces Pombe ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
Specific Inhibitor ◽  
Copper Transport ◽  
Nuclear Accumulation ◽  
Wild Type ◽  
High Copper

ABSTRACT In this study, we examine the fate of the nuclear pool of the Schizosaccharomyces pombe transcription factor Cuf1 in response to variations in copper levels. A nuclear pool of Cuf1-green fluorescent protein (GFP) was generated by expressing a functional cuf1 + -GFP allele in the presence of a copper chelator. We then extinguished cuf1 + -GFP expression and tracked the changes in the localization of the nuclear pool of Cuf1-GFP in the presence of low or high copper concentrations. Treating cells with copper as well as silver ions resulted in the nuclear export of Cuf1. We identified a leucine-rich nuclear export signal (NES), 349LAALNHISAL358, within the C-terminal region of Cuf1. Mutations in this sequence abrogated Cuf1 export from the nucleus. Furthermore, amino acid substitutions that impair Cuf1 NES function resulted in increased target gene expression and a concomitant cellular hypersensitivity to copper. Export of the wild-type Cuf1 protein was inhibited by leptomycin B (LMB), a specific inhibitor of the nuclear export protein Crm1. We further show that cells expressing a temperature-sensitive mutation in crm1 + exhibit increased nuclear accumulation of Cuf1 at the nonpermissive temperature. Although wild-type Cuf1 is localized in the nucleus in both conditions, we observed that the protein can still be inactivated by copper, resulting in the repression of ctr4 + gene expression in the presence of exogenous copper. These results demonstrate that nuclear accumulation of Cuf1 per se is not sufficient to cause the unregulated expression of the copper transport genes like ctr4 + . In addition to nuclear localization, a functional Cys-rich domain or NES element in Cuf1 is required to appropriately regulate copper transport gene expression in response to changes in intracellular copper concentration.

scholarly journals KLF3 Represses the Inflammatory Response in Macrophages

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-36
Author(s):  
Jessica M Salmon ◽  
Casie Leigh Reed ◽  
Maddyson Bender ◽  
Helen Lorraine Mitchell ◽  
Vanessa Fox ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Time Course ◽  
Target Genes ◽  
Wild Type ◽  
Cell Counts ◽  
Inflammatory Macrophages

Krüppel-like factors (KLFs) are a family of transcription factors that play essential roles in the development and differentiation of the hematopoietic system. These transcription factors possess highly conserved C-terminal zinc-finger motifs, which enable their binding to GC-rich, or CACC-box, motifs in promoter and enhancer regions of target genes. The N-terminal domains of these proteins are more varied and mediate the recruitment of various co-factors, which can form a complex with either activator or repressor function. Acting primarily as a gene repressor through its recruitment of CtBPs and histone deacetylases (HDACs) [1], we have recently shown that KLF3 competes with KLF1 bound sites in the genome to repress gene expression during erythropoiesis [2]. However, the function of Klf3 in other lineages has been less well studied. This widely expressed transcription factor has reported roles in the differentiation of marginal zone B cells, eosinophil function and inflammation [3]. We utilised the Klf3-null mouse model [4] to more closely examine the role of Klf3 in innate inflammatory cells. These mice exhibit elevated white cell counts, including monocytes (Figure 1A), and inflammation of the skin. Conditional knockout of Klf4 in myeloid cells leads to a deficiency of inflammatory macrophages [5]. To test our hypothesis KLF3 normally represses inflammation, perhaps by antagonising the action of KLF4, bone-marrow derived macrophages (BMDM) were generated from wild-type or Klf3-null mice and stimulated with the bacterial toxin lipopolysaccharide (LPS). In wild type BMDM, LPS induces Klf3 gene expression and activation then delayed repression of target genes such as Lgals3 (galectin-3) over a 21 hour time course (Figure 1B). Quantitative real-time PCR and mRNA-seq of WT v Klf3-null macrophages identified ~100 differentially expressed genes involved in proliferation, macrophage activation and inflammation. We transduced the monocyte cell line, RAW264.7 (that expresses Klf4, Klf3 and Klf2), with a retroviral vector expressing a tamoxifen-inducible KLF3-ER fusion construct. KLF3 induced cell cycle arrest and macrophage differentiation. We will report on KLF3-induced gene expression changes (repression and activation), and ChIP-seq for KLF3, in RAW cells. The results shed light on the mechanism by which KLF3 normally represses monocyte/macrophage responses to infection. This study highlights the importance of key transcriptional regulators that tightly control gene expression during inflammation. Loss of Klf3 leads to alterations in this process, resulting in hyper-activation of inflammatory macrophages, increased white cell counts and inflammation of the skin. A greater knowledge of the inflammatory process and how it is regulated is important for our understanding of acute infection and inflammatory disease. Further studies are planned to investigate the role of the KLF3 transcription factor in response to inflammation in vivo. References: 1. Pearson, R., et al., Kruppel-like transcription factors: A functional family. Int J Biochem Cell Biol, 2007. W2. Ilsley, M.D., et al., Kruppel-like factors compete for promoters and enhancers to fine-tune transcription. Nucleic Acids Res, 2017. 45(11): p. 6572-6588. W3. Knights, A.J., et al., Kruppel-like factor 3 (KLF3) suppresses NF-kappaB-driven inflammation in mice. J Biol Chem, 2020. 295(18): p. 6080-6091. W4. Sue, N., et al., Targeted disruption of the basic Kruppel-like factor gene (Klf3) reveals a role in adipogenesis. Mol Cell Biol, 2008. 28(12): p. 3967-78. W5. Alder, J.K., et al., Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J Immunol, 2008. 180(8): p. 5645-52. Figure 1: Elevated WCC (A) and inflammatory markers (B) in BMDM after LPS stimulation. 1. Total WCC in adult mice (3-6 months old) of the indicated genotypes. There is a statistically significant increase in the WCC in Klf3-/- v wild type mice (P<0.001 by student's t test). B. Time course (hours) after LPS stimulation of confluent BMDM. Klf3 is induced 3-fold by LPS and KLF3-target genes such as Lgals3 are not fully repressed by 21 hours in knockout mice. Figure 1 Disclosures Perkins: Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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