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At least 1,153 records · Page 64Linked to original sources
PubMed2006

Transcriptional regulation of megakaryopoiesis: thrombopoietin signaling and nuclear factors.

PURPOSE OF REVIEW: Thrombopoietin, the primary regulator of megakaryopoiesis, acts by modulating several nuclear transcription factors. This review focuses on recent studies that have provided new insights into the functional roles of these proteins. RECENT FINDINGS: Among the transcription factors responsible for megakaryopoiesis, important roles for the signal transducer and activator of transcription and Forkhead box proteins have been defined. In addition, in the past several years, two new groups of transcription factors have been found to be affected by thrombopoietin signaling, homeodomain-containing HOX proteins and hypoxia-inducible factor. The HOX transcription factors, which play key roles in body pattern development, are also expressed in adult hematopoietic stem cells and play pivotal roles in their proliferation. Thrombopoietin controls the levels of expression and modifies the function of homeodomain proteins in thrombopoietin-responsive leukemic cells and in primary immature hematopoietic cells. Levels of hypoxia-inducible factor, a master transcription factor required for the adaptation to hypoxic conditions, is also affected by thrombopoietin in these cells. SUMMARY: The discovery that a diverse range of transcription factors are downstream effectors of thrombopoietin helps to explain the molecular mechanisms by which the hormone affects hematopoiesis.

Animals↗
PubMed2025

Gene model for the ortholog of foxo in Drosophila sechellia.

Gene model for the ortholog of forkhead box, sub-group O (foxo) in the May 2011 (Broad dsec_caf1/DsecCAF1) Genome Assembly (GenBank Accession: GCA_000005215.1) of Drosophila sechellia. This ortholog was characterized as part of a developing dataset to study the evolution of the Insulin/insulin-like growth factor signaling pathway (IIS) across the genus Drosophila using the Genomics Education Partnership gene annotation protocol for Course-based Undergraduate Research Experiences.

Bioinformatics↗
PubMed2025

FoxP3 forms a head-to-head dimer in vivo and stabilizes its multimerization on adjacent microsatellites.

FoxP3, the master regulator of Tregs, employs two DNA-binding modes to recognize diverse DNA sequences. It multimerizes on long TnG repeats (n = 2-5) to bridge DNA segments and stabilize chromatin loops, and it forms head-to-head (H-H) dimers on inverted repeat forkhead motifs (IR-FKHM) without bridging DNA. Although genomic data confirm its multimeric role, in vivo evidence for H-H dimerization has been elusive. Here, unbiased pull-down sequencing uncovers a range of relaxed motifs that drive H-H dimerization, enabling systematic genome-wide analysis. We demonstrate that FoxP3 binds genomic DNA as both H-H dimers and multimers in Tregs, with H-H binding often seeding and stabilizing multimerization on adjacent TnG repeats-especially on shorter, suboptimal repeats. While multimerization is conserved across FoxP family members, H-H dimerization is unique to FoxP3 orthologs, conferred by its divergent accessory loop. This dual-mode strategy broadens FoxP3's sequence repertoire and enhances its architectural function in chromatin looping.

Journal Article↗
PubMed2005

Starvation and oxidative stress resistance in Drosophila are mediated through the eIF4E-binding protein, d4E-BP.

eIF4E, the mRNA 5' cap-binding protein, is regulated by its binding protein (4E-BP), a downstream target of phosphatidylinositol-3-OH kinase [PI(3)K] signaling. We show that Drosophila 4E-BP (d4E-BP) activity becomes critical for survival under dietary restriction and oxidative stress, and is linked to life span. The Drosophila forkhead transcription factor (dFOXO) activates d4E-BP transcription. We show that ectopic expression of d4E-BP in dFOXO-null flies restores oxidative stress resistance to control levels. Thus, d4E-BP is an important downstream effector of a dFOXO phenotype, and regulation of translation by eIF4E is vital during environmental stress.

Aging↗
PubMed2006

Insulin-like signaling and the neural circuit for integrative behavior in C. elegans.

Caenorhabditis elegans exhibits a food-associated behavior that is modulated by the past cultivation temperature. Mutations in INS-1, the homolog of human insulin, caused the defect in this integrative behavior. Mutations in DAF-2/insulin receptor and AGE-1/phosphatidylinositol 3 (PI-3)-kinase partially suppressed the defect of ins-1 mutants, and a mutation in DAF-16, a forkhead-type transcriptional factor, caused a weak defect. In addition, mutations in the secretory protein HEN-1 showed synergistic effects with INS-1. Expression of AGE-1 in any of the three interneurons, AIY, AIZ, or RIA, rescued the defect characteristic of age-1 mutants. Calcium imaging revealed that starvation induced INS-1-mediated down-regulation of AIZ activity. Our results suggest that INS-1, in cooperation with HEN-1, antagonizes the DAF-2 insulin-like signaling pathway to modulate interneuron activity required for food-associated integrative behavior.

Animals↗
PubMed1994

Localized expression of sloppy paired protein maintains the polarity of Drosophila parasegments.

During germ-band extension in the Drosophila embryo, intercellular communication is required to maintain gene expression patterns initiated at cellular blastoderm. For example, the wingless (wg) single-cell-wide stripe in each parasegment (PS) is dependent on a signal from the adjacent, posterior cells, which express engrailed (eN). This signal is thought to be the hedgehog (hh) gene product, which antagonizes the activity of patched (ptc), a repressor of wg expression. Genetic evidence indicates that the hh signal is bidirectional, but wg transcription is only derepressed on the anterior side of the en/hh stripes. To explain the asymmetric response of the wg promoter to the hh signal, current models predict that each PS is divided into cells that are competent to express either wg or en, but not both. The sloppy paired (slp) locus contains two transcription units, both encoding proteins containing a forkhead domain, a DNA-binding motif. Removal of slp gene function causes embryos to exhibit a severe pair-rule/segment polarity phenotype. We show that the en stripes expand anteriorly in slp mutant embryos and that slp activity is an absolute requirement for maintenance of wg expression at the same time that wg transcription is dependent on hh. The slp proteins are expressed in broad stripes just anterior of the en-positive cells, overlapping the narrow wg stripes. We propose that by virtue of their ability to activate wg and repress en expression, the distribution of the slp proteins define the wg-competent and en-competent groups. Consistent with this hypothesis, ubiquitous expression of slp protein throughout the PS abolishes en expression and, in ptc mutant embryos, results in a near ubiquitous distribution of wg transcripts. In addition to demonstrating the role of slp in maintaining segment polarity, our results suggest that slp works in, or parallel with, the ptc/hh signal transduction pathway to regulate wg transcription.

Animals↗
PubMed2001

Crystallization and preliminary X-ray diffraction studies of FHA domains of Dun1 and Rad53 protein kinases.

Forkhead-associated (FHA) domains are modular protein-protein interaction domains of approximately 130 amino acids present in numerous signalling proteins. FHA-domain-dependent protein interactions are regulated by phosphorylation of target proteins and FHA domains may be multifunctional phosphopeptide-recognition modules. FHA domains of the budding yeast cell-cycle checkpoint protein kinases Dun1p and Rad53p have been crystallized. Crystals of the Dun1-FHA domain exhibit the symmetry of the space group P6(1)22 or P6(5)22, with unit-cell parameters a = b = 127.3, c = 386.3 A; diffraction data have been collected to 3.1 A resolution on a synchrotron source. Crystals of the N-terminal FHA domain (FHA1) of Rad53p diffract to 4.0 A resolution on a laboratory X-ray source and have Laue-group symmetry 4/mmm, with unit-cell parameters a = b = 61.7, c = 104.3 A.

Animals↗
PubMed2005

Mycobacterium tuberculosis serine/threonine kinases PknB, PknD, PknE, and PknF phosphorylate multiple FHA domains.

The physiologic roles and the substrates of the Mycobacterium tuberculosis (Mtb) serine/threonine kinases are largely unknown. Here, we report six novel interactions of PknB, PknD, PknE, and PknF with the Forkhead-Associated (FHA) domains of Rv0020c and the putative ABC transporter Rv1747. Purified PknB and PknF kinase domains phosphorylated multiple FHA-domain proteins in vitro. Although they remain to be verified in vivo, these reactions suggest a web of interactions between STPKs and FHA domains.

ATP-Binding Cassette Transporters↗
PubMed2006

Regulatory T cells in the periphery.

Recognition of a systemic antigen by CD4+ T cells in a lymphopenic host leads to the sequential generation of pathogenic effector cells and protective CD25+ forkhead box protein (Foxp3+) regulatory T cells (Tregs) in the periphery. Such an experimental model is potentially valuable for defining the stimuli that determine the balance of effector and regulatory T cells. Our studies have shown that interleukin-2 (IL-2) enhances the development of effector cells and is essential for the peripheral generation of regulatory cells. Other models of peripheral Treg generation suggest that the concentration of antigen, the nature of the antigen-presenting cells, and cytokines such as transforming growth factor-beta and IL-10 may all influence the peripheral generation of Tregs.

Animals↗
PubMed2007

The interleukin-10 inducing effect of transforming growth factor-beta on human naive CD4+ T cells from cord blood is restricted to the TH1 subset.

Transforming growth factor (TGF-beta) seems to play a role in the regulation of immune responses, mainly by its suppressive function towards cells of the immune system. However, both in mice and human, conflicting data are published on the capacity of TGF-beta to induce interleukin (IL)-10 secretion in both naive and skewed T cell populations. Our aim was to test the IL-10-inducing capacity of TGF-beta in both naive and skewed cord blood mononuclear cells (CBMCs) and elucidate the mechanism by which TGF-beta exerts its effect. Therefore, naive CBMCs and CBMCs during skewing under T helper 1 (Th1) and Th2 polarizing conditions were stimulated with CD3 and/or CD28 in the presence or absence of TGF-beta. Proliferation, cytokine production and mRNA expression of transcription factors was measured. TGF-beta enhanced the IL-10 production in Th1 and naive cells only, and suppressed the T(H)1 phenotype as demonstrated in cytokine levels and T-box expression in T cells (T-bet) expression. Interestingly, forkhead box p3 (Foxp3) expression tended to increase in both Th1 and Th2 cells. These data indicate that TGF-beta can induce a regulatory phenotype in both naive and Th1-polarized cells derived from cord blood. The induction of IL-10 was not observed in Th2-polarized phenotype, indicating that TGF-beta might be especially of interest for immunomodulation in Th1 cells.

Antigens, CD↗
PubMed2005

CD4CD25 regulatory T lymphocytes in allergy and asthma.

Allergic asthma is characterized by airway hyper-responsiveness and chronic mucosal inflammation mediated by CD4(+) Th2 lymphocytes. Regulatory CD4(+)CD25(+) T cells are important components of the homeostasis of the immune system, as impaired CD4(+)CD25(+) T cell activity can cause autoimmune diseases and allergy. The mechanism of suppression by CD4(+)CD25(+) T cells remains controversial; different in vivo and in vitro studies raise possible roles for the immunosuppressive cytokines interleukin-10 and transforming growth factor-beta, forkhead transcription factor Foxp3, glucocorticoid-induced tumor necrosis factor receptor, cytotoxic lymphocyte associated antigen-4, 4-1BB costimulator receptor, a CD4-related molecule LAG-3, and neuropilin-1. Current data suggest that Th2 responses to allergens are normally suppressed by CD4(+)CD25(+) T cells. Suppression by CD4(+)CD25(+) T cells is decreased in allergic individuals. Furthermore, CD4(+)CD25(+) T cells play a key role in regulating airway eosinophilic inflammation. The immunomodulatory properties of CD4(+)CD25(+) T cells do extend to Th2 responses, most notably by limiting the development of a proinflammatory CD4(+) Th2 phenotype characterized by reduced cytokine production. An understanding of the roles of CD4(+)CD25(+) T cells in vivo could provide better insight into the design of novel approaches to modulate the chronic airway inflammatory reaction evident in bronchial asthma.

Asthma↗
PubMedDate not supplied

Developmental expression of transcription factor genes in a demosponge: insights into the origin of metazoan multicellularity.

Demosponges are considered part of the most basal evolutionary lineage in the animal kingdom. Although the sponge body plan fundamentally differs from that of other metazoans, their development includes many of the hallmarks of bilaterian and eumetazoan embryogenesis, namely fertilization followed by a period of cell division yielding distinct cell populations, which through a gastrulation-like process become allocated into different cell layers and patterned within these layers. These observations suggest that the last common ancestor (LCA) to all living animals was developmentally more sophisticated than is widely appreciated and used asymmetric cell division and morphogen gradients to establish localized populations of specified cells within the embryo. Here we demonstrate that members of a range of transcription factor gene classes, many of which appear to be metazoan-specific, are expressed during the development of the demosponge Reniera, including ANTP, Pax, POU, LIM-HD, Sox, nuclear receptor, Fox (forkhead), T-box, Mef2, and Ets genes. Phylogenetic analysis of these genes suggests that not only the origin but the diversification of some of the major developmental metazoan transcription factor classes took place before sponges diverged from the rest of the Metazoa. Their expression during demosponge development suggests that, as in today's sophisticated metazoans, these genes may have functioned in the regulatory network of the metazoan LCA to control cell specification and regionalized gene expression during embryogenesis.

Amino Acid Sequence↗
PubMed2006

Microarray analysis of transcription factor gene expression in melatonin-treated human peripheral blood mononuclear cells.

The existence of specific melatonin-binding sites in lymphoid cells led to the discovery of signal transduction pathway for melatonin in human lymphocytes and immunomodulatory role of melatonin in immune cells. In recent years, transcriptional regulation of melatonin on various transcription factors has been demonstrated. Therefore, this study was designed to assess by cDNA microarray analysis the regulatory effects of melatonin on transcription factors in human peripheral blood mononuclear cells (PBMCs). Forty-six genes were upregulated and 23 were downregulated more than twofold in melatonin-treated PBMCs. Of the more than twofold upregulated transcription factor genes, homeo box A4 (HOXA4), forkhead box O1A (FOXO1A), transcription elongation factor B (SIII), polypeptide 3 (TCEB3), and peroxisome proliferative activated receptor delta (PPARD) were identified. Of the more than twofold downregulated genes, PHD finger protein 15 (PHF15) and zinc finger protein 33a (ZNF33A) were identified. In summary, identification of these genes by cDNA microarray analysis in response to melatonin administration may provide a foundation for further studies on the function of melatonin in human PBMCs.

Base Sequence↗
PubMed2006

Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells.

The prevalence of diabetes has exponentially increased in recent decades due to environmental factors such as nocturnal lifestyle and aging, both of which influence the amount of melatonin produced in the pineal gland. The present study investigated the effect of melatonin on signaling pathways of glucose transport in C2C12 mouse skeletal muscle cells. Intriguingly, treatment of C2C12 cells with melatonin (1 nm) stimulated glucose uptake twofold increase. Melatonin-stimulated glucose transport was inhibited with co-treatment with the melatonin receptor antagonist luzindole. Furthermore, treatment of stably over-expressed melatonin receptor type 2B containing C2C12 myotubes with melatonin amplified glucose transport c. 13-fold. Melatonin also increased the phosphorylation level of insulin receptor substrate-1 (IRS-1) and the activity of phosphoinositide 3-kinase (PI-3-kinase). However, 3',5'-cyclic adenosine monophosphate-activated protein kinase (AMPK), another important glucose transport stimulatory mediator via an insulin-independent pathway, was not influenced by melatonin treatment. Activity of p38 mitogen-activated protein kinase (MAPK), a downstream mediator of AMPK, was also not changed by melatonin. In addition, melatonin increased the expression level of forkhead box A2, which was recently discovered to regulate fatty acid oxidation and to be inhibited by insulin. In summary, melatonin stimulates glucose transport to skeletal muscle cells via IRS-1/PI-3-kinase pathway, which implies, at the molecular level, its role in glucose homeostasis and possibly in diabetes. Additionally, exposure to light at night and aging, both of which lower endogenous melatonin levels may contribute to the incidence and/or development of diabetes.

Biological Transport↗
PubMed2004

Attenuation of small-for-size liver graft injury by FTY720: significance of cell-survival Akt signaling pathway.

To investigate the protective mechanism of FTY720 in small-for-size liver grafts, we applied a rat orthotopic liver transplantation model using 40% of liver grafts. FTY720 was administered (1 mg/kg, i.v.) at 20 min before graft harvesting in the donor, immediately before total hepatectomy and immediately after graft reperfusion in the recipient. The 7-day graft survival rates in the FTY720 group were significantly improved compared with the control group [100% (6/6) vs. 40% (4/10), p = 0.034]. FTY720 significantly reduced serum ALT and AST levels at 24 h after liver transplantation. The cell-survival Akt signaling pathway was activated in FTY720 groups by phosphorylation of Glycogen Synthase Kinase-3beta, Bad and Forkhead Transcription Factor at 6 and 24 h after liver transplantation. The cleaved-caspases 3, 7 and 9 were down-regulated, accompanied with less apoptotic nuclei after FTY720 treatment. Acute-phase inflammatory MAPK pathway was down-regulated by dephosphorylation of c-Raf, Mek and Erk in the treatment groups. A20 and endothelial nitric oxide synthase were up-regulated together with down-regulation of iNOS. Hepatic sinusoids were well preserved in the FTY720 group but disrupted in the control group. In conclusion, FTY720 attenuates small-for-size liver graft injury by activation of cell-survival Akt signaling and down-regulation of the MAPK pathway.

Alanine Transaminase↗
PubMed2005

Development of Caenorhabditis elegans pharynx, with emphasis on its nervous system.

The Caenorhabditis elegans pharynx is a neuromuscular tube of which the function is to pump and crush bacteria, and inject them into the intestine. The 80-cell pharynx develops via the morphogenesis and differentiation of the cells that compose its semi-spherical primordium, and requires the activity of several evolutionarily conserved genes, such as pha-4 (the homolog to the Drosophila forkhead and vertebrate FoxA), ceh-22 (the homolog to the Drosophila tinman and vertebrate Nkx2.5), and pha-2 (the homolog to the vertebrate Hex). There are 20 neurons in the pharynx, each with a reproducible unique trajectory. Developmental genetic analysis of axon guidance in the pharynx indicates that some axon trajectories are in part established without growth cones, whereas other parts necessitate growth cone function and guidance. Here we provide an overview of the developmental genetics of the Caenorhabditis elegans pharynx, with an emphasis on its nervous system.

Animals↗
PubMed2000

Regulation of the Clara cell secretory protein/uteroglobin promoter in lung.

Clara cell secretory protein/uteroglobin (CCSP/UG) is specifically expressed in the conducting airway epithelium of the lung in a differentiation-dependent manner. The proximal promoter region of the rodent CCSP/UG gene directs Clara cell specificity. Previously, it was shown that the forkhead transcription factors HNF-3 alpha and beta and the homeodomain factor TTF-1 are important transcription factors acting through this region, suggesting that they contribute to cell specificity of the CCSP/UG gene. Members of the C/EBP family of transcription factors can also interact with elements of the proximal rat and mouse CCSP/UG promoters. The onset of C/EBP alpha expression in Clara cells correlates with the strong increase of CCSP/UG expression. Thus, C/EBP alpha may play a crucial role for differentiation-dependent CCSP/UG expression. Transfection studies demonstrate that C/EBP alpha and TTF-1 can synergistically activate the murine CCSP/UG promoter. Altogether, these results suggest that C/EBP alpha, TTF-1, and HNF-3 determine the Clara cell-specific, differentiation-dependent expression of the CCSP/UG gene in murine lung. The relative importance of these three transcription factors, however, differs in rabbits and humans.

Animals↗
PubMed2000

Molecular genetic mechanisms of life span manipulation in Caenorhabditis elegans.

Aging and a limited life span are fundamental biological realities. Recent studies have demonstrated that longevity can be manipulated and have revealed molecular mechanisms underlying longevity control in the soil nematode Caenorhabditis elegans. Signals from both neurons and the gonad appear to negatively regulate longevity. One tissue-specific signal involves an insulin-like phosphatidylinositol 3-OH kinase pathway, dependent upon the DAF-16 forkhead transcription factor. These signals regulate mechanisms determining longevity that include the OLD-1 (formerly referred to as TKR-1) receptor tyrosine kinase. Interestingly, increased resistance to environmental stress shows a strong correlation with life extension.

Animals↗