Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors

2003 ◽  
Vol 31 (1) ◽  
pp. 292-297 ◽  
Author(s):  
K.U. Birkenkamp ◽  
P.J. Coffer
Keyword(s):  
Transcription Factors ◽  
Cell Survival ◽  
Cell Fate ◽  
Nuclear Export ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Acute Lymphocytic Leukaemia ◽  
Cell Fate Decisions ◽  
Forkhead Transcription Factors ◽  
Forkhead Box

Recently, the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors has been identified as direct targets of phosphoinositide 3-kinase-mediated signal transduction. The AFX (acute-lymphocytic-leukaemia-1 fused gene from chromosome X), FKHR (Forkhead in rhabdomyosarcoma) and FKHR-L1 (FKHR-like 1) transcription factors are directly phosphorylated by protein kinase B, resulting in nuclear export and inhibition of transcription. This signalling pathway was first identified in the nematode worm Caenorhabditis elegans, where it has a role in regulation of the life span of the organism. Studies have shown that this evolutionarily conserved signalling module has a role in regulation of both cell-cycle progression and cell survival in higher eukaryotes. These effects are co-ordinated by FOXO-mediated induction of a variety of specific target genes that are only now beginning to be identified. Interestingly, FOXO transcription factors appear to be able to regulate transcription through both DNA-binding-dependent and -independent mechanisms. Our understanding of the regulation of FOXO activity, and defining specific transcriptional targets, may provide clues to the molecular mechanisms controlling cell fate decisions to divide, differentiate or die.

scholarly journals A High-Content Screen Identifies Inhibitors of Nuclear Export of Forkhead Transcription Factors

2011 ◽  
Vol 16 (4) ◽  
pp. 394-404 ◽  
Author(s):  
David C. Bouck ◽  
Peter Shu ◽  
Jimmy Cui ◽  
Anang Shelat ◽  
Taosheng Chen
Keyword(s):  
Transcription Factors ◽  
Nuclear Export ◽  
Cell Cycle Progression ◽  
Akt Signaling Pathway ◽  
Cycle Progression ◽  
Forkhead Transcription Factors ◽  
Forkhead Box ◽  
Therapeutic Value ◽  
Isoform Specificity ◽  
Foxo Transcription Factors

Class O forkhead box (FOXO) transcription factors are downstream targets of the PI3K/AKT signaling pathway, which is upregulated in many tumors. AKT phosphorylates and inactivates FOXO1 by relocating it to the cytoplasm. Because FOXO1 functions as a tumor suppressor by negatively regulating cell cycle progression and cell survival, compounds that promote FOXO1 localization to the nucleus might have therapeutic value in oncology. Here the authors describe the identification of such compounds by using an image-based, high-content screen. Compounds that were active in retaining FOXO1 in the nucleus were tested to determine their pathway specificity and isoform specificity by using high-content assays for Rev and FOXO3, respectively.

scholarly journals Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marina Farkas ◽  
Hideharu Hashimoto ◽  
Yingtao Bi ◽  
Ramana V. Davuluri ◽  
Lois Resnick-Silverman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Binding ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Binding Modes ◽  
Cell Fate Decisions ◽  
Cycle Arrest

AbstractThe tumor suppressor p53 integrates stress response pathways by selectively engaging one of several potential transcriptomes, thereby triggering cell fate decisions (e.g., cell cycle arrest, apoptosis). Foundational to this process is the binding of tetrameric p53 to 20-bp response elements (REs) in the genome (RRRCWWGYYYN0-13RRRCWWGYYY). In general, REs at cell cycle arrest targets (e.g. p21) are of higher affinity than those at apoptosis targets (e.g., BAX). However, the RE sequence code underlying selectivity remains undeciphered. Here, we identify molecular mechanisms mediating p53 binding to high- and low-affinity REs by showing that key determinants of the code are embedded in the DNA shape. We further demonstrate that differences in minor/major groove widths, encoded by G/C or A/T bp content at positions 3, 8, 13, and 18 in the RE, determine distinct p53 DNA-binding modes by inducing different Arg248 and Lys120 conformations and interactions. The predictive capacity of this code was confirmed in vivo using genome editing at the BAX RE to interconvert the DNA-binding modes, transcription pattern, and cell fate outcome.

scholarly journals Nuclear Export Is Evolutionarily Conserved in CVC Paired-Like Homeobox Proteins and Influences Protein Stability, Transcriptional Activation, and Extracellular Secretion

2005 ◽  
Vol 25 (7) ◽  
pp. 2573-2582 ◽  
Author(s):  
Shirley K. Knauer ◽  
Gert Carra ◽  
Roland H. Stauber
Keyword(s):  
Transcription Factors ◽  
Protein Stability ◽  
Cell Fate ◽  
Transcriptional Activation ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
Nucleocytoplasmic Transport ◽  
Cell Fate Decisions ◽  
Extracellular Secretion ◽  
Export Signal

ABSTRACT Homeodomain transcription factors control a variety of essential cell fate decisions during development. To understand the developmental regulation by these transcription factors, we describe here the molecular analysis of paired-like CVC homeodomain protein (PLC-HDP) trafficking. Complementary experimental approaches demonstrated that PLC-HDP family members are exported by the Crm1 pathway and contain an evolutionary conserved leucine-rich nuclear export signal. Importantly, inactivation of the nuclear export signal enhanced protein stability, resulting in increased transactivation of transfected reporters and decreased extracellular secretion. In addition, PLC-HDPs harbor a conserved active nuclear import signal that could also function as a protein transduction domain. In our study, we characterized PLC-HDPs as mobile nucleocytoplasmic shuttle proteins with the potential for unconventional secretion and intercellular transfer. Nucleocytoplasmic transport may thus represent a conserved control mechanism to fine-tune the transcriptional activity of PLC-HDPs prerequisite for regulating and maintaining the complex expression pattern during development.

scholarly journals PRMT6 activates cyclin D1 expression in conjunction with the transcription factor LEF1

Oncogenesis ◽  
2021 ◽  
Vol 10 (5) ◽  
Author(s):  
Lucas Schneider ◽  
Stefanie Herkt ◽  
Lei Wang ◽  
Christine Feld ◽  
Josephine Wesely ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Transcription Factors ◽  
Cyclin D1 ◽  
Cell Fate ◽  
Target Genes ◽  
Specific Gene ◽  
Cell Fate Decisions ◽  
Rational Development ◽  
Differentiation And Proliferation

AbstractThe establishment of cell type specific gene expression by transcription factors and their epigenetic cofactors is central for cell fate decisions. Protein arginine methyltransferase 6 (PRMT6) is an epigenetic regulator of gene expression mainly through methylating arginines at histone H3. This way it influences cellular differentiation and proliferation. PRMT6 lacks DNA-binding capability but is recruited by transcription factors to regulate gene expression. However, currently only a limited number of transcription factors have been identified, which facilitate recruitment of PRMT6 to key cell cycle related target genes. Here, we show that LEF1 contributes to the recruitment of PRMT6 to the central cell cycle regulator CCND1 (Cyclin D1). We identified LEF1 as an interaction partner of PRMT6. Knockdown of LEF1 or PRMT6 reduces CCND1 expression. This is in line with our observation that knockdown of PRMT6 increases the number of cells in G1 phase of the cell cycle and decreases proliferation. These results improve the understanding of PRMT6 activity in cell cycle regulation. We expect that these insights will foster the rational development and usage of specific PRMT6 inhibitors for cancer therapy.

scholarly journals CDK12 is Necessary to Promote Epidermal Differentiation through Transcription Elongation

2021 ◽  
Author(s):  
George Sen ◽  
Jingting Li ◽  
Manisha Tiwari ◽  
Yifang Chen
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Cell Fate ◽  
Target Genes ◽  
Skin Diseases ◽  
Transcription Elongation ◽  
The Body ◽  
Epidermal Differentiation ◽  
Transcription Control ◽  
Cell Fate Decisions

Proper differentiation of the epidermis is essential to prevent water loss and to protect the body from the outside environment. Perturbations in this process can lead to a variety of skin diseases that impacts 1 in 5 people. While transcription factors that control epidermal differentiation have been well characterized, other aspects of transcription control such as elongation are poorly understood. Here we show that of the two cyclin dependent kinases (CDK12 and CDK13), that are known to regulate transcription elongation, only CDK12 is necessary for epidermal differentiation. Depletion of CDK12 led to loss of differentiation gene expression and absence of skin barrier formation in regenerated human epidermis. CDK12 binds to genes that code for differentiation promoting transcription factors (GRHL3, KLF4, and OVOL1) and is necessary for their elongation. CDK12 is necessary for elongation by promoting Ser2 phosphorylation on the C-terminal domain of RNA polymerase II and the binding of the elongation factor SPT6 to target genes. Our results suggest that control of transcription elongation by CDK12 plays a prominent role in adult cell fate decisions.

scholarly journals Heme Oxygenase-1 at the Nexus of Endothelial Cell Fate Decision Under Oxidative Stress

2021 ◽  
Vol 9 ◽  
Author(s):  
Sindhushree Raghunandan ◽  
Srinivasan Ramachandran ◽  
Eugene Ke ◽  
Yifei Miao ◽  
Ratnesh Lal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Stress Response ◽  
Cell Surface ◽  
Cell Survival ◽  
Cell Fate ◽  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Heme Oxygenase 1 ◽  
Cell Fate Decisions

Endothelial cells (ECs) form the inner lining of blood vessels and are central to sensing chemical perturbations that can lead to oxidative stress. The degree of stress is correlated with divergent phenotypes such as quiescence, cell death, or senescence. Each possible cell fate is relevant for a different aspect of endothelial function, and hence, the regulation of cell fate decisions is critically important in maintaining vascular health. This study examined the oxidative stress response (OSR) in human ECs at the boundary of cell survival and death through longitudinal measurements, including cellular, gene expression, and perturbation measurements. 0.5 mM hydrogen peroxide (HP) produced significant oxidative stress, placed the cell at this junction, and provided a model to study the effectors of cell fate. The use of systematic perturbations and high-throughput measurements provide insights into multiple regimes of the stress response. Using a systems approach, we decipher molecular mechanisms across these regimes. Significantly, our study shows that heme oxygenase-1 (HMOX1) acts as a gatekeeper of cell fate decisions. Specifically, HP treatment of HMOX1 knockdown cells reversed the gene expression of about 51% of 2,892 differentially expressed genes when treated with HP alone, affecting a variety of cellular processes, including anti-oxidant response, inflammation, DNA injury and repair, cell cycle and growth, mitochondrial stress, metabolic stress, and autophagy. Further analysis revealed that these switched genes were highly enriched in three spatial locations viz., cell surface, mitochondria, and nucleus. In particular, it revealed the novel roles of HMOX1 on cell surface receptors EGFR and IGFR, mitochondrial ETCs (MTND3, MTATP6), and epigenetic regulation through chromatin modifiers (KDM6A, RBBP5, and PPM1D) and long non-coding RNA (lncRNAs) in orchestrating the cell fate at the boundary of cell survival and death. These novel aspects suggest that HMOX1 can influence transcriptional and epigenetic modulations to orchestrate OSR affecting cell fate decisions.

FoxO transcription factors in oxidative stress response and ageing – a new fork on the way to longevity?

2008 ◽  
Vol 389 (3) ◽  
pp. 279-283 ◽  
Author(s):  
Daniel G. Sedding
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Cellular Effects ◽  
Forkhead Box ◽  
Foxo Transcription Factors

Abstract Forkhead box O (FoxO) transcription factors are important downstream targets of the PI3K/Akt signaling pathway and crucial regulators of cell fate. This function of FoxOs relies on their ability to control diverse cellular functions, including proliferation, differentiation, apoptosis, DNA repair, defense against oxidative stress and ageing. FoxOs are regulated by a variety of different growth factors and hormones, and their activity is tightly controlled by post-translational modifications, including phosphorylation, acetylation, ubiquitination and interaction with different proteins and transcription factors. This brief review focuses on the molecular mechanisms, cellular effects and resulting organismal phenotypes generated by differentially regulated FoxO proteins and discusses our current understanding of the role of FoxOs in disease and ageing processes.

scholarly journals The Interplay Between Chromatin Architecture and Lineage-Specific Transcription Factors and the Regulation of Rag Gene Expression

2021 ◽  
Vol 12 ◽  
Author(s):  
Kazuko Miyazaki ◽  
Masaki Miyazaki
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Fate Decisions ◽  
Chromatin Architecture ◽  
Cell Type Specific

Cell type-specific gene expression is driven through the interplay between lineage-specific transcription factors (TFs) and the chromatin architecture, such as topologically associating domains (TADs), and enhancer-promoter interactions. To elucidate the molecular mechanisms of the cell fate decisions and cell type-specific functions, it is important to understand the interplay between chromatin architectures and TFs. Among enhancers, super-enhancers (SEs) play key roles in establishing cell identity. Adaptive immunity depends on the RAG-mediated assembly of antigen recognition receptors. Hence, regulation of the Rag1 and Rag2 (Rag1/2) genes is a hallmark of adaptive lymphoid lineage commitment. Here, we review the current knowledge of 3D genome organization, SE formation, and Rag1/2 gene regulation during B cell and T cell differentiation.

Molecular Mechanisms Underlying the Regulation of Alternate Macrophage and Neutrophil Gene Programs by the Egr Transcription Factors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4773-4773
Author(s):  
Jason X Cheng ◽  
Peter Laslo ◽  
Chauncey Spooner ◽  
Eric Bertolino ◽  
Harinder Singh
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Gene Activity ◽  
Gene Promoters ◽  
Cell Fate Determination ◽  
Fate Determination ◽  
Gene Regulatory ◽  
Progenitor Cell Line

Abstract Cell fate determination in the hematopoietic system involves the onset and resolution of mixed lineage patterns of gene expression. Molecular mechanisms underlying the concerted activation and repression of alternate lineage genes remain to be elucidated. We have proposed a gene regulatory network for macrophage development in which the transcription factors PU.1 and the Egr’s function in a feed forward loop to activate macrophage genes. In the network, the Egr’s counteract the neutrophil regulator Gfi-1 and also repress alternate lineage genes. Using mutant alleles of Egr-1 and Egr-2 we validate the model and demonstrate that the Egr’s are required for initiating but not maintaining the repression of neutrophil genes during macrophage differentiation. Employing a PU.1−/− progenitor cell line we show that PU.1 transiently binds to and activates both macrophage and neutrophil gene promoters thereby leading to the onset of mixed lineage gene activity. While inducing macrophage cell fate determination, PU.1 remains persistently bound to macrophage gene promoters aided by the Egr’s. Surprisingly, the Egr’s displace PU.1 from neutrophil gene promoters by interacting with a co-repressor Nab-2 thereby repressing the alternate lineage program. We propose that the Egr’s have evolved to molecularly discriminate distinct sets of target genes and delineate divergent patterns of gene activity.

scholarly journals High Energy Intake Induced Overexpression of Transcription Factors and Its Regulatory Genes Involved in Acceleration of Hepatic Lipogenesis: A Rat Model for Type 2 Diabetes

Biomedicines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 76 ◽  
Author(s):  
Suresh P. Khadke ◽  
Aniket A. Kuvalekar ◽  
Abhay M. Harsulkar ◽  
Nitin Mantri
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factors ◽  
Glucose Tolerance ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
High Energy ◽  
Tolerance Test ◽  
Diabetic Control ◽  
Ppar Γ

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by impaired insulin action and its secretion. The objectives of the present study were to establish an economical and efficient animal model, mimicking pathophysiology of human T2DM to understand probable molecular mechanisms in context with lipid metabolism. In the present study, male Wistar rats were randomly divided into three groups. Animals were fed with high fat diet (HFD) except healthy control (HC) for 12 weeks. After eight weeks, intra peritoneal glucose tolerance test was performed. After confirmation of glucose intolerance, diabetic control (DC) group was injected with streptozotocin (STZ) (35 mg/kg b.w., i.p.). HFD fed rats showed increase (p ≤ 0.001) in glucose tolerance and HOMA-IR as compared to HC. Diabetes rats showed abnormal (p ≤ 0.001) lipid profile as compared to HC. The hepatocyte expression of transcription factors SREBP-1c and NFκβ, and their target genes were found to be upregulated, while PPAR-γ, CPT1A and FABP expressions were downregulated as compared to the HC. A number of animal models have been raised for studying T2DM, but the study has been restricted to only the biochemical level. The model is validated at biochemical, molecular and histopathological levels, which can be used for screening new therapeutics for the effective management of T2DM.

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